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2.  Appropriateness of hydroxyethylcellulose gel as a placebo control in vaginal microbicide trials: A comparison of the two control arms of HPTN 035 
Objective
To compare the two control arms of HPTN 035 (a hydroxyethylcellulose (HEC) gel control arm and a no gel control arm) to assess behavioral effects associated with gel use and direct causal effects of the HEC gel on STIs, pregnancy, and genital safety.
Design
Randomized trial with one blinded (HEC gel) and one open label (no gel) control arms.
Methods
HIV-uninfected, sexually active women were randomized into the HEC gel arm (n=771) and into the no gel arm (n=772) in five countries. Participants in the HEC gel arm were instructed to insert the study gel intravaginally <1 hour before each vaginal sex act. Data on sexual behavior, adherence, safety, pregnancy, and STIs were collected quarterly for 12 to 30 months of follow-up.
Results
During follow-up, mean reported condom use in the past week was significantly higher in the no gel arm (81% versus 70%, p<0.001). There were no significant differences, after adjusting for this differential condom use, between the two arms in rates of genital safety events, pregnancy outcomes, or STIs, including HIV-1.
Conclusions
In this large randomized trial, we found no significant differences between the no gel and HEC gel arms in rates of genital safety events, pregnancy outcomes, or STIs. These results aid interpretation of the results of previous vaginal microbicide trials that used the HEC gel as a control. The HEC gel is suitable as a control for ongoing and future vaginal microbicide studies.
doi:10.1097/QAI.0b013e31828607c5
PMCID: PMC3625489  PMID: 23334506
HIV prevention; vaginal microbicide; placebo; women; sexually transmitted infections
3.  Assessing Adherence in the CAPRISA 004 Tenofovir Gel HIV Prevention Trial: Results of a Nested Case–Control Study 
AIDS and Behavior  2014;18:826-832.
Adherence undeniably impacts product effectiveness in microbicide trials, but the connection has proven challenging to quantify using routinely collected behavioral data. We explored this relationship using a nested case–control study in the CAPRISA 004 Tenofovir (TFV) gel HIV prevention trial. Detailed 3-month recall data on sex events, condom and gel use were collected from 72 incident cases and 205 uninfected controls. We then assessed how the relationship between self-reported adherence and HIV acquisition differed between the TFV and placebo gel groups, an interaction effect that should exist if effectiveness increases with adherence. The CAPRISA 004 trial determined that randomization to TFV gel was associated with a significant reduction in risk of HIV acquisition. In our nested case–control study, however, we did not observe a meaningful decrease in the relative odds of infection—TFV versus placebo—as self-reported adherence increased. To the contrary, exploratory sub-group analysis of the case–control data identified greater evidence for a protective effect of TFV gel among participants reporting less than 80 % adherence to the protocol-defined regimen (odds ratio (OR) 0.30; 95 % CI 0.11–0.78) than among those reporting ≥80 % adherence (Odds Ratio 0.81; 95 % CI 0.34–1.92). The small number of cases may have inhibited our ability to detect the hypothesized interaction between adherence and effectiveness. Nonetheless, our results re-emphasize the challenges faced by investigators when adherence may be miss-measured, miss-reported, or confounded with the risk of HIV.
doi:10.1007/s10461-014-0753-8
PMCID: PMC3984418  PMID: 24647763
Microbicides; Tenofovir gel; Adherence; HIV prevention; Self-report
4.  Rapid, complex adaption of transmitted HIV-1 full-length genomes in subtype C-infected individuals with differing disease progression 
AIDS (London, England)  2013;27(4):507-518.
Objective(s)
There is limited information on full-length genome sequences and the early evolution of transmitted HIV-1 subtype C viruses, which constitute the majority of viruses spread in Africa. The purpose of this study was to characterize the earliest changes across the genome of subtype C viruses following transmission, to better understand early control of viremia.
Design
We derived the near full-length genome sequence responsible for clinical infection from five HIV subtype C-infected individuals with different disease progression profiles and tracked adaption to immune responses in the first six months of infection.
Methods
Near full-length genomes were generated by single genome amplification and direct sequencing. Sequences were analyzed for amino acid mutations associated with cytotoxic T-lymphocyte (CTL) or antibody (Ab)-mediated immune pressure, and for reversion.
Results
Fifty-five sequence changes associated with adaptation to the new host were identified with 38% attributed to CTL pressure; 35% to antibody pressure; 16% to reversions and the remainder were unclassified. Mutations in CTL epitopes were most frequent in the first 5 weeks of infection, with the frequency declining over time with the decline in viral load. CTL escape predominantly occurred in nef, followed by pol and env. Shuffling/toggling of mutations was identified in 81% of CTL epitopes with only 7% reaching fixation within the six month period.
Conclusions
There was rapid virus adaptation following transmission, predominantly driven by CTL pressure, with most changes occurring during high viremia. Rapid escape and complex escape pathways provide further challenges for vaccine protection.
doi:10.1097/QAD.0b013e32835cab64
PMCID: PMC3720865  PMID: 23370465
HIV-1; Africa; genome; acute infection; cytotoxic T-lymphocytes; progression
5.  HIV incidence in young girls in KwaZulu-Natal, South Africa-Public health imperative for their inclusion in HIV biomedical intervention trials 
AIDS and behavior  2012;16(7):1870-1876.
Young women are particularly vulnerable for acquiring HIV yet they are often excluded from clinical trials testing new biomedical intervention. We assessed the HIV incidence and feasibility of enrolling a cohort of young women for potential participation in future clinical trials. Between March 2004 and May 2007, 594 HIV uninfected 14–30 year old women were enrolled into a longitudinal HIV risk reduction study in KwaZulu-Natal, South Africa. The overall HIV prevalence at screening in young girls below the age of 18 years of age was 27.6% compared to 52.0% in the women above 18 years, p<0.001. HIV incidence was 4.7 [95% Confidence interval (CI) 1.5–10.9) and 6.9 (95% CI 4.8–9.6)/100 women years (wy), p=0.42 and pregnancy rates were 23.7 (95% CI 14.9–35.9) and 16.4 (95% CI 12.9–20.6)/100wy, p=0.29, in the women below and above 18 years respectively. Retention was similar in both groups (71.0% versus 71.5%, p=0.90). This study demonstrates that the inclusion of young girls between the ages of 14 and 17 years in longitudinal studies is feasible and their inclusion in clinical trials would maintain scientific integrity and power of the study.
doi:10.1007/s10461-012-0209-y
PMCID: PMC3460144  PMID: 22618892
young girls; biomedical HIV prevention research; South Africa
6.  Immune Reconstitution Inflammatory Syndrome following Antiretroviral Therapy Initiation in Tuberculosis Patients: Findings from the SAPiT Trial 
Annals of internal medicine  2012;157(5):313-324.
Background
Concerns about immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during anti-tuberculosis treatment in co-infected patients.
Objective
We assessed IRIS incidence, severity, and outcomes relative to timing of ART initiation in patients with HIV-related tuberculosis (HIV-TB).
Setting
An outpatient clinic in Durban, South Africa
Patients
642 HIV-TB co-infected patients
Design
In a secondary analysis of the SAPiT trial, IRIS was assessed in patients randomized to initiate ART either within four weeks of tuberculosis treatment initiation (early integrated-treatment arm), within four weeks of completion of the intensive phase of tuberculosis treatment (late integrated-treatment arm) or within four weeks after tuberculosis therapy completion (sequential-treatment arm). IRIS was defined as new onset or worsening symptoms, signs or radiographic manifestations temporally related to treatment initiation accompanied by a treatment response. IRIS severity, hospitalization and time to resolution were monitored.
Results
IRIS incidence was 19.5 (n=43), 7.5 (n=18) and 8.1 (n=19) per 100 person-years in the early integrated-, late integrated-, and sequential-treatment arms, respectively; P < 0.001, and 45.5, 9.7 and 19.7 per 100 person-years in patients with baseline CD4+ counts <50 cells/mm3, P = 0.004. IRIS incidence was higher in the early integrated- compared to the late integrated- (incidence rate ratio (IRR) = 2.6, 95%confidence interval (CI): 1.5 to 4.8; P < 0.001) or sequential-treatment arm (IRR=2.4, 95%CI: 1.4 to 4.4; P < 0.001). IRIS cases in the early integrated-treatment arm were more severe (34.9% vs. 18.9%, P = 0.18); had significantly higher hospitalization rates (18/43 vs. 5/37; P = 0.01), and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) compared to IRIS cases in the other two arms.
Limitation
IRIS could not be assessed, due to LTFU, withdrawal or death within 6 months of scheduled ART initiation, in more patients from the sequential treatment arm (n=74) than in the late integrated treatment arm (n=50) and in the early integrated treatment arm (n=32). This study did not assess IRIS risk in non-ambulant patients and in patients with extra-pulmonary and smear negative pulmonary tuberculosis.
Conclusion
Initiation of ART early during tuberculosis treatment resulted in significantly higher IRIS rates, with longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings, particularly relevant to patients initiating ART with CD4+ counts < 50 cells/mm3, need to be considered together with the increased survival benefit of early ART initiation in this group. Clintrials.gov: NCT00398996
doi:10.7326/0003-4819-157-5-201209040-00004
PMCID: PMC3534856  PMID: 22944873
7.  No Evidence for Selection of HIV-1 with Enhanced Gag-Protease or Nef Function among Breakthrough Infections in the CAPRISA 004 Tenofovir Microbicide Trial 
PLoS ONE  2013;8(8):e71758.
Background
Use of antiretroviral-based microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial.
Methods and Results
We isolated the earliest available gag-protease and nef gene sequences from 83 individuals and examined their in vitro function using recombinant viral replication capacity assays and surface protein downregulation assays, respectively. No major phylogenetic clustering and no significant differences in gag-protease or nef function were observed in participants who received tenofovir gel versus placebo gel prophylaxis.
Conclusion
Results indicate that the partial protective effects of 1% tenofovir gel use in the CAPRISA 004 trial were not offset by selection of transmitted/early HIV-1 variants with enhanced Gag-Protease or Nef fitness.
doi:10.1371/journal.pone.0071758
PMCID: PMC3756015  PMID: 24015191
8.  CAPRISA 004 Tenofovir Microbicide Trial: No Impact of Tenofovir Gel on the HIV Transmission Bottleneck 
Alterations of the genital mucosal barrier may influence the number of viruses transmitted from a human immunodeficiency virus–infected source host to the newly infected individual. We used heteroduplex tracking assay and single-genome sequencing to investigate the effect of a tenofovir-based microbicide gel on the transmission bottleneck in women who seroconverted during the CAPRISA 004 microbicide trial. Seventy-seven percent (17 of 22; 95% confidence interval [CI], 56%–90%) of women in the tenofovir gel arm were infected with a single virus compared with 92% (13 of 14; 95% CI, 67%–>99%) in the placebo arm (P = .37). Tenofovir gel had no discernable impact on the transmission bottleneck.
doi:10.1093/infdis/jis305
PMCID: PMC3415934  PMID: 22551813
9.  Preservation HIV-1-specific IFNγ+ CD4+ T cell responses in breakthrough infections following exposure to Tenofovir Gel in the CAPRISA 004 microbicide trial 
The CAPRISA004 trial demonstrated reduction of sexual HIV-1 acquisition in women using a vaginal microbicide containing tenofovir. A better understanding of the consequences of antiretroviral-containing microbicides for immune responses in individuals with intercurrent HIV-1 infection is needed for future trials combining the use of microbicides with HIV-1 vaccines. Investigation of immune responses in women who acquired HIV-1 whilst using tenofovir gel showed significantly higher (p=0.01) Gag-specific IFNγ+ CD4+ T-cell responses. The use of tenofovir containing gel around the time of infection can modulate HIV-1 immunity, and these immunological changes need to be considered in future trials combining vaccines and microbicides.
doi:10.1097/QAI.0b013e31824f53a9
PMCID: PMC3381429  PMID: 22362152
HIV-1; vaginal microbicide; tenofovir; HIV-1-specific CD4+ T cell help
10.  A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection 
Introduction
More than a million people acquire HIV infection annually. Pre-exposure prophylaxis (PrEP) using antiretrovirals is currently being investigated for HIV prevention. Oral and topical formulations of tenofovir have undergone pre-clinical and clinical testing to assess acceptability, safety and effectiveness in preventing HIV infection.
Areas covered
The tenofovir drug development pathway from compound discovery; pre-clinical animal model testing and human testing were reviewed for safety, tolerability, and efficacy. Tenofovir is well tolerated and safe when used both systemically or applied topically for HIV prevention. High drug concentrations at the site of HIV transmission and concomitant low systemic drug concentrations are achieved with vaginal application. Coitally applied gel may be the favoured prevention option for women compared to the tablets which may be more suitable for prevention in men and sero-discordant couples. However, recent contradictory effectiveness outcomes in women need to be better understood.
Expert opinion
Emerging evidence has brought new hope that antiretrovirals can potentially change the course of the HIV epidemic when used as early treatment for prevention, as topical or oral PrEP. Although some trial results appear conflicting, behavioral factors, adherence to dosing, and pharmacokinetic properties of the different tenofovir formulations and dosing approaches offer plausible explanations for most of the variations in effectiveness observed in different trials.
doi:10.1517/13543784.2012.667072
PMCID: PMC3460694  PMID: 22394224
ART; NtRTI; tenofovir; tenofovir disoproxil fumarate; HIV prevention; microbicide; PMPA – [9-R-(2-Phosphonomethoxypropyl) adenine]
11.  Increased memory differentiation is associated with decreased polyfunctionality for HIV but not for CMV-specific CD8+ T cells 
The generation of polyfunctional CD8+ T cells, in response to vaccination or natural infection, has been associated with improved protective immunity. However, it is unclear whether the maintenance of polyfunctionality is related to particular cellular phenotypic characteristics. To determine whether the cytokine expression profile is linked to the memory differentiation stage, we analyzed the degree of polyfunctionality of HIV-specific CD8+ T cells within different memory subpopulations in 20 ART-naïve HIV-1 infected individuals at approximately 34 weeks post infection. These profiles were compared with CMV-specific CD8+ T cell responses in HIV-uninfected controls and in individuals chronically infected with HIV. Our results showed that the polyfunctional abilities of HIV-specific CD8+ T cells differed according to their memory phenotype. Early-differentiated cells (CD45RO+CD27+) exhibited a higher proportion of cells positive for three or four functions (p<0.001), and a lower proportion of mono-functional cells (p<0.001) compared to terminally-differentiated (CD45RO−CD27−) HIV-specific CD8+ T cells. The majority of terminally-differentiated HIV-specific CD8+ T cells were mono-functional (median 69% [IQR: 57–83]), producing predominantly CD107a or MIP1β. Moreover, proportions of HIV-specific mono-functional CD8+ T cells positively associated with proportions of terminally-differentiated HIV-specific CD8+ T cells (p=0.019, r=0.54). In contrast, CMV-specific CD8+ T cell polyfunctional capacities were similar across all memory subpopulations, with terminally- and early-differentiated cells endowed with comparable polyfunctionality. Overall, these data show that the polyfunctional abilities of HIV-specific CD8+ T cells are influenced by the stage of memory differentiation, which is not the case for CMV-specific responses.
doi:10.4049/jimmunol.1201488
PMCID: PMC3466366  PMID: 22966086
12.  Co-enrollment in multiple HIV prevention trials – Experiences from the CAPRISA 004 Tenofovir gel trial 
Contemporary clinical trials  2011;32(3):333-338.
Background
In settings where multiple HIV prevention trials are conducted in close proximity, trial participants may attempt to enroll in more than one trial simultaneously. Co-enrollment impacts on participant’s safety and validity of trial results. We describe our experience, remedial action taken, inter-organizational collaboration and lessons learnt following the identification of co-enrolled participants.
Experiences
Between February and April 2008, we identified 185 of the 398 enrolled participants as ineligible. In violation of the study protocol exclusion criteria, there was simultaneous enrollment in another HIV prevention trial (ineligible co-enrolled, n=135), and enrollment of women who had participated in a microbicide trial within the past 12 months (ineligible not co-enrolled, n=50). Following a complete audit of all enrolled participants, ineligible participants were discontinued via study exit visits from trial follow-up. Custom-designed education program on co-enrollment impacting on participants’ safety and validity of the trial results were implemented. Shared electronic database between research units were established to enable verification of each volunteer’s trial participation and to prevent future co-enrollments.
Lessons Learnt
Interviews with ineligible enrolled women revealed that high-quality care; financial incentives; altruistic motives; preference for sex with gel; wanting to increase their likelihood of receiving active gel; perceived low risk of discovery and peer pressure as the reasons for their enrolment in the CAPRISA 004 trial.
Conclusion
Instituting education programs based on the reasons reported by women for seeking enrolment in more than one trial and using a shared central database system to identify co-enrollments have effectively prevented further co-enrollments.
doi:10.1016/j.cct.2011.01.005
PMCID: PMC3616246  PMID: 21278001
HIV prevention trials; co-enrollment; young women
13.  HIV prevention transformed: the new prevention research agenda 
Lancet  2011;378(9787):269-278.
SUMMARY
We have entered a new era in HIV prevention whereby priorities have expanded from biomedical discovery to include implementation, effectiveness, and the effect of combination prevention at the population level. However, gaps in knowledge and implementation challenges remain. In this Review we analyse trends in the rapidly changing landscape of HIV prevention, and chart a new path for HIV prevention research that focuses on the implementation of effective and efficient combination prevention strategies to turn the tide on the HIV pandemic.
doi:10.1016/S0140-6736(11)60877-5
PMCID: PMC3606928  PMID: 21763938
14.  Design challenges facing clinical trials of the effectiveness of new HIV prevention technologies 
AIDS (London, England)  2012;26(5):529-532.
Recent successes of antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV infection have raised questions whether further placebo controlled trials of new HIV-prevention technologies are ethically justifiable. A trial with active agent(s) in the comparator group can be designed either as a superiority or non-inferiority trial. In a non-inferiority trial the hypothesis tested is that the intervention is not inferior to, by a predefined clinically relevant amount, or at least as effective as, the comparator. Non-inferiority trials pose challenges in data interpretation.
Firstly it is possible to show equivalence of two non-effective interventions. If the active comparator intervention is ineffective, the new intervention would be shown to be non-inferior to this inactive intervention, while neither intervention is superior to placebo or no intervention. The second challenge is that any effect that dilutes the true efficacy of an intervention in a trial, such as non-adherence, loss to follow-up or protocol violations, makes it easier for the two interventions to be declared equivalent. Non-differential low adherence is unlikely to lead to the conclusion that an inferior intervention is non-inferior. However, differential adherence between study arms, which is more likely in non-blinded trials, is likely to bias the results and lead to incorrect conclusions.
Investigators conducting non-inferiority trials will have to pay special attention to supporting, measuring and maintaining high adherence. The goal in future non-inferiority trials should be to maintain similar levels of high adherence in all study arms, but at a minimum to reduce the likelihood of differential adherence across study arms.
doi:10.1097/QAD.0b013e3283509a29
PMCID: PMC3442788  PMID: 22210638
15.  Changes in Natural Killer Cell Activation and Function during Primary HIV-1 Infection 
PLoS ONE  2013;8(1):e53251.
Background
Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection.
Methodology/Principal Findings
Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α4β7). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p<0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32'p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIRpos) NK cells increased following HIV acquisition (p = 0.006), and KIRpos NK cells were less activated than KIRneg NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001).
Conclusions/Significance
Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.
doi:10.1371/journal.pone.0053251
PMCID: PMC3541400  PMID: 23326405
16.  Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape 
Nature medicine  2012;18(11):1688-1692.
Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful1-3, a minority of individuals naturally develop these antibodies after many years of infection4-7. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly underrepresented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.
doi:10.1038/nm.2985
PMCID: PMC3494733  PMID: 23086475
17.  Short Communication Decreased Incidence of Dual Infections in South African Subtype C-Infected Women Compared to a Cohort Ten Years Earlier 
AIDS Research and Human Retroviruses  2011;27(11):1167-1172.
Abstract
Previously, we determined the incidence of dual infections in a South African cohort and its association with higher viral setpoint. Ten years later, we compare the incidence and impact of dual infections at transmission on viral setpoint in a geographically similar cohort (n =  46) making use of both the heteroduplex mobility assay (HMA) and the more recent single genome amplification (SGA) approach. HIV incidence was lower in this cohort (7% compared to 18%), and we find a similar reduction in the number of dual infections (9% compared to 19%). Unlike the previous study, there was no association between either dual infection (n =  4) or multivariant transmission (n =  7) and disease progression. This study emphasized the importance of monitoring changes in the HIV epidemic as it may have important ramifications on our understanding of the natural history of disease.
doi:10.1089/aid.2010.0162
PMCID: PMC3206740  PMID: 21198409
18.  APOBEC3G Expression is Dysregulated in Primary HIV-1 Infection and a Polymorphic Variant Influences CD4+ T Cell Counts and Plasma Viral Load 
AIDS (London, England)  2010;24(2):195-204.
Objectives
In the absence of HIV-1 Vif, cellular cytosine deaminases such as APOBEC3G, inhibit the virus by inducing hypermutations on viral DNA, among other mechanisms of action. We investigated the association of APOBEC3G mRNA levels and APOBEC3G genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4+ T cell counts as outcomes.
Methods
Study subjects were 250 South African females at high risk for HIV-1C infection. We used quantitative real-time PCR to measure the expression of APOBEC3G in HIV−ve and HIV+ve primary infection samples. APOBEC3G variants were identified by DNA re-sequencing and TaqMan genotyping.
Results
We found no correlation between APOBEC3G expression levels and plasma viral loads (r=0.053, p=0.596) or CD4+ T cell counts (r=0.030, p=0.762) in 32 seroconverters. However, APOBEC3G expression levels were significantly higher in HIV−ve individuals compared to HIV+ve individuals (p<0.0001), including matched pre- and post infection samples from the same individuals (n=13, p<0.0001). 25 single nucleotide polymorphisms (SNPs), nine of which were novel, were identified within APOBEC3G by re-sequencing followed by genotyping of 168 individuals. The H186R mutation, a codon changing variant in exon 4, was associated with high viral loads (p=0.0097) and decreased CD4+ T cell levels (p=0.0081).
Conclusions
These data suggest that APOBEC3G transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3G expression levels in PBMCs do not correlate with viral loads or CD4+ T cell counts. However, structural variation of APOBEC3G may significantly affect early HIV-1 pathogenesis, although the mechanism remains unclear and warrants further investigation.
doi:10.1097/QAD.0b013e3283353bba
PMCID: PMC3470914  PMID: 19996938
APOBEC3G; HIV-1 C; Primary Infection; mRNA Expression; Polymorphisms; Host proteins
19.  Contraceptive Choices, Pregnancy Rates, and Outcomes in a Microbicide Trial 
Obstetrics and gynecology  2011;118(4):895-904.
Objective
Women who become pregnant during the conduct of biomedical HIV prevention trials are taken off the study product for safety reasons. High pregnancy rates can compromise statistical integrity in these trials. The comprehensive contraceptive curriculum developed for the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial was evaluated for its ability to enhance contraceptive uptake, reduce pregnancy rates, and preserve statistical integrity.
Methods
Contraceptive- and pregnancy-related eligibility criteria were specified in the protocol. We enrolled women who opted for a non-barrier method of contraceptive and provided hormonal contraceptives on-site at no cost. At each monthly study visit, we provided pregnancy prevention counselling and performed pregnancy testing. Study product was withheld on pregnancy diagnosis, but women continued with monthly follow-up.
Results
Contraceptive usage was high throughout the study with 100% uptake at baseline and 94.71% use after a mean of 18 months follow-up at exit. Injectable progestins, particularly medroxyprogesterone acetate, remained the preferred choice of contraceptive. After 30 months of follow-up, 54 pregnancies were reported out of 889 participants, giving a pregnancy incidence rate of 3.95 per 100 woman-years (95% CI: 2.96 to 5.17). Of all pregnancies, 2/3 (64.81%) resulted in a full-term live birth, while 18.52% and 11.11% pregnancies culminated as miscarriage and terminated pregnancies, respectively. There were no congenital anomalies in the early neonatal period. Pregnancies resulted in 1.56% of woman-years of study follow-up lost due to temporary product withdrawal.
Conclusion
The CAPRISA 004 contraceptive curriculum was an effective strategy for maintaining low pregnancy rates, thereby minimizing product withdrawal and loss of follow-up time.
doi:10.1097/AOG.0b013e31822be512
PMCID: PMC3178043  PMID: 21934454
20.  Uptake of Provider Initiated HIV Testing and Counseling among women attending an urban Sexually Transmitted Disease Clinic in South Africa- missed opportunities for early diagnosis of HIV infection 
AIDS care  2010;22(5):533-537.
Summary
This study assessed the uptake of Provider Initiated HIV Testing and Counseling (PITC) amongst women attending an urban sexually transmitted diseases (STD) clinic in South Africa. From July 2005 to June 2006, women were offered HIV testing following group information and education on HIV and STDs in the clinic waiting area. Of those who were provided with education, information and offered HIV testing, uptake was 43.5% (2439/5612). The overall HIV prevalence among those tested was 56.5% and the prevalence of acute HIV infection was 1.2%. Of the 56.5% (3173/5612) refusing to test, the reasons for not testing were having already been tested for HIV (61.8%), being afraid to test or felt unready to test (32.5%), the need to consult with partner (0.9%) and refusing with no explanation (4.2%). In settings where high risk patients await health care services, such as an STD clinic, failure to implement PITC is a missed opportunity for patients to benefit from counseling, prevention, early diagnosis and referral into care and treatment for HIV infection.
doi:10.1080/09540120903254005
PMCID: PMC3457004  PMID: 20397075
Provider initiated HIV counseling and testing; STD clinic; HIV prevention and treatment
21.  Association of Polymorphisms in the LEDGF/p75 Gene (PSIP1) with Susceptibility to HIV-1 Infection and Disease Progression 
AIDS (London, England)  2011;25(14):1711-1719.
Objective
LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans.
Methods
Integrase binding domain (IBD) of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs, SNP1-SNP4 and one exonic SNP, SNP5 were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV-1 IN was measured by AlphaScreen.
Results
rs2277191A was more frequent among seropositives (p=0.06, Fisher's exact test), and among individuals followed longitudinally trended towards association with higher likelihood of HIV-1 acquisition (RH=2.21, p=0.08; Cox model) and it was also associated with rapid disease progression (RH=5.98, p=0.04; Cox model). rs12339417C was associated with slower decline of CD4+ T cell (p=0.02) and lower levels of LEDGF/p75 (p<0.01). Seroconverters had higher preinfection levels of LEDGF/p75 (p<0.01) but levels decreased after HIV infection (p=0.02).
Conclusions
Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts.
doi:10.1097/QAD.0b013e328349c693
PMCID: PMC3233670  PMID: 21681054
22.  Safety and Effectiveness of BufferGel and 0.5% PRO2000 Gel for the Prevention of HIV Infection in Women 
AIDS (London, England)  2011;25(7):957-966.
Objective
To determine the safety and effectiveness of BufferGel and 0.5% PRO2000 microbicide gels for the prevention of male to female HIV transmission
Design
Phase II/IIb, randomized, placebo-controlled trial with three double-blinded gel arms and an open label no gel arm.
Methods
Study participants from Malawi, South Africa, Zambia, Zimbabwe and USA were instructed to apply study gel ≤1 hour before each sex act and safety, sexual behavior, pregnancy, gel adherence, acceptability, and HIV serostatus were assessed during follow-up.
Results
The 3101 enrolled women were followed for an average of 20.4 months with 93.6% retention and 81.1% self-reported gel adherence. Adverse event rates were similar in all study arms. HIV incidence rates in the 0.5% PRO2000 Gel, BufferGel, Placebo Gel and No Gel arms were 2.70, 4.14, 3.91 and 4.02 per 100 women-years, respectively. HIV incidence in the 0.5% PRO2000 Gel arm was lower than the Placebo Gel arm (Hazard Ratio (HR)=0.7; p=0.10) and the No Gel arm (HR=0.67; p=0.06). HIV incidence rates were similar in the BufferGel and both Placebo Gel (HR=1.10; p=0.63) and No Gel control arms (HR=1.05; p=0.78). HIV incidence was similar in the Placebo Gel and No Gel arms (HR=0.97; p=0.89).
Conclusions
0.5% PRO2000 Gel demonstrated a modest 30% reduction in HIV acquisition in women. However, these results were not statistically significant and subsequent findings from the MDP 301 trial have confirmed that 0.5% PRO2000 has little or no protective effect. BufferGel did not alter the risk of HIV infection. Both products were safe.
doi:10.1097/QAD.0b013e32834541d9
PMCID: PMC3083640  PMID: 21330907
Microbicide; PRO 2000 Gel; BufferGel; HIV Prevention; Women
23.  The future role of rectal and vaginal microbicides to prevent HIV infection in heterosexual populations: implications for product development and prevention 
Sexually Transmitted Infections  2011;87(7):646-653.
Objectives
To compare the potential impact of rectal(RMB), vaginal(VMB) and bi-compartment(RVMB) (applied vaginally and protective during vaginal and anal intercourse) microbicides to prevent HIV in various heterosexual populations. To understand when a RMB is as useful than a VMB for females practicing anal intercourse(AI).
Methods
Mathematical model was used to assess the population-level impact (cumulative fraction of new HIV infections prevented(CFP)) of the 3 different microbicides in various intervention scenarios and prevalence settings. We derived the break-even RMB efficacy required to reduce a female’s cumulative risk of HIV infection by the same amount than a VMB.
Results
Under optimistic coverage (fast roll-out, 100% uptake), a 50% efficacious VMB used in 75% of sex acts in population without AI may prevent ~33%[27,42%] new total (males and females combined) HIV infections over 25 years. The 25-year CFP reduces to ~25%[20,32%] and 17% [13,23%] if uptake decreases to 75% and 50%, respectively. Similar loss of impact (by 25–50%) is observed if the same VMB is introduced in populations with 5–10% AI and for RRRAI=4–20. A RMB is as useful as a VMB (i.e. break-even) in populations with 5% AI if RRRAI=20, and in populations with 15–20% AI if RRRAI=4, independently of adherence as long as it is the same with both products. The 10-year CFP with a RVMB is 2-fold larger than for a VMB or RMB when AI=10% and RRRAI=10.
Conclusion
Even low AI frequency can compromise the impact of VMB interventions. RMB and RVMB will be important prevention tools for heterosexual populations.
doi:10.1136/sextrans-2011-050184
PMCID: PMC3332062  PMID: 22110117
24.  Interleukin-10 Promoter Polymorphisms Influence HIV-1 Susceptibility and Primary HIV-1 Pathogenesis 
The Journal of infectious diseases  2009;200(3):448-452.
IL-10 directly inhibits HIV-1 replication but it may also promote viral persistence by inactivation of effector immune mechanisms. Here we show in an African cohort that individuals with genotypes associated with high IL-10 production at two promoter single nucleotide polymorphisms (-1082 and -592) were less likely to become HIV-1 infected, but had significantly higher median plasma viral loads during the acute phase (≤ 3 months post infection). However, as the infection progressed, the hierarchical genotype/median viral load pattern was reversed. Thus IL-10 may influence HIV-1 susceptibility and pathogenesis but effects on the latter may differ according to the infection phase.
doi:10.1086/600072
PMCID: PMC3137931  PMID: 19534595
IL-10; HIV-1 subtype C; viral load; HIV-1 susceptibility; HIV-1 pathogenesis
25.  Association of TRIM22 with the Type 1 Interferon Response and Viral Control during Primary HIV-1 Infection▿  
Journal of Virology  2010;85(1):208-216.
Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-α, IFN-β, myxovirus resistance protein A (MxA), human TRIM5α (huTRIM5α), and TRIM22 mRNA levels in peripheral blood mononuclear cells (PBMCs) of high-risk, HIV-1-uninfected participants and HIV-1-positive study participants. Samples were available for 32 uninfected subjects and 28 infected persons, all within 1 year of infection. HIV-1-positive participants had higher levels of IFN-β (P = 0.0005), MxA (P = 0.007), and TRIM22 (P = 0.01) and lower levels of huTRIM5α (P < 0.001) than did HIV-1-negative participants. TRIM22 but not huTRIM5α correlated positively with type 1 IFN (IFN-α, IFN-β, and MxA) (all P < 0.0001). In a multivariate model, increased MxA expression showed a significant positive association with viral load (P = 0.0418). Furthermore, TRIM22 but not huTRIM5α, IFN-α, IFN-β, or MxA showed a negative correlation with plasma viral load (P = 0.0307) and a positive correlation with CD4+ T-cell counts (P = 0.0281). In vitro studies revealed that HIV infection induced TRIM22 expression in PBMCs obtained from HIV-negative donors. Stable TRIM22 knockdown resulted in increased HIV-1 particle release and replication in Jurkat reporter cells. Collectively, these data suggest concordance between type 1 IFN and TRIM22 but not huTRIM5α expression in PBMCs and that TRIM22 likely acts as an antiviral effector in vivo.
doi:10.1128/JVI.01810-10
PMCID: PMC3014203  PMID: 20980524

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