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1.  Kaposi Sarcoma–Associated Herpesvirus (KSHV) Seroprevalence in Population-Based Samples of African Children: Evidence for At Least 2 Patterns of KSHV Transmission 
The Journal of infectious diseases  2009;200(3):430-438.
Background
Kaposi sarcoma–associated herpesvirus (KSHV) infection is endemic among adult populations in Africa. A prevailing view is that childhood transmission is primarily responsible for the high seroprevalence of KSHV among adults that is observed throughout the continent. However, few studies have directly examined children, particularly in locations where KS is not commonly endemic.
Methods
Participants were children aged 1.5−8.9 years, including 427 children from a population-based sample in South Africa, 422 from a population-based sample in Uganda, and 567 from a clinic-based sample in Uganda. All serum specimens were tested by the same laboratory for KSHV antibodies with use of 2 enzyme immunoassays (against K8.1 and ORF65) and 1 immunofluorescence assay.
Results
KSHV seroprevalence was 7.5%−9.0% among South African children and was not associated with age. In contrast, in the Ugandan population-based sample, KSHV seroprevalence increased from 10% among 2-year-old children to 30.6% among 8-year-old children (Ptrend < .001). In the Ugandan clinic-based sample, seroprevalence increased from 9.3% among 2-year-old children to 36.4% among 8-year-old children (Ptrend < .001).
Conclusion
Two distinct relationships between age and KSHV infection among children imply that KSHV transmission among children is not uniform throughout Africa and is therefore not always responsible for the high seroprevalence observed in adults. There are at least 2 patterns of KSHV transmission in Africa.
doi:10.1086/600103
PMCID: PMC3975590  PMID: 19534596
2.  Use of Saliva as a Lubricant in Anal Sexual Practices Among Homosexual Men 
Objectives
Compared with other sexually active adults, men who have sex with men (MSM) are more frequently infected with several pathogens including cytomegalovirus, hepatitis B virus, and Kaposi sarcoma-associated herpesvirus. Because one common element between these organisms is their presence in saliva, we evaluated saliva exposure among MSM in a heretofore relatively unrecognized route—via use of saliva as a lubricant in anal sex.
Methods
MSM in a San Francisco population–based cohort were interviewed regarding use of saliva by the insertive partner as a lubricant in various anal sexual practices.
Results
Among 283 MSM, 87% used saliva as a lubricant in insertive or receptive penile–anal intercourse or fingering/fisting at some point during their lifetime; 31%–47% did so, depending upon the act, in the prior 6 months. Saliva use as a lubricant was more common among younger men and among HIV-infected men when with HIV-infected partners. Even among MSM following safe sex guidelines by avoiding unprotected penile–anal intercourse, 26% had anal exposure to saliva via use as a lubricant.
Conclusions
Among MSM, use of saliva as a lubricant is a common, but not ubiquitous, practice in anal sex. The findings provide the rationale for formal investigation of whether saliva use in this way contributes to transmission of saliva-borne pathogens in MSM.
doi:10.1097/QAI.0b013e31819388a9
PMCID: PMC3975591  PMID: 19131893
homosexual; saliva; lubricant; anal intercourse
3.  AIDS Alters the Commensal Plasma Virome 
Journal of Virology  2013;87(19):10912-10915.
We compared the plasma viromes of HIV-infected subjects with low versus high CD4+ T cell counts from the United States and Uganda by using deep sequencing and detected HIV, hepatitis C virus, hepatitis B virus, GB virus C, anellovirus, and human endogenous retrovirus (HERV) reads. An increase in the proportion of reads for anelloviruses, a family of highly prevalent and genetically diverse human viruses, was seen in subjects with AIDS from both countries. The proportion of endogenous human retrovirus reads was increased in AIDS subjects from Uganda but not the United States. Progression to AIDS is therefore associated with changes in the plasma concentration of commensal viruses.
doi:10.1128/JVI.01839-13
PMCID: PMC3807392  PMID: 23903845
4.  Changes in food insecurity, nutritional status, and physical health status after antiretroviral therapy initiation in rural Uganda 
Objective
To investigate whether time on antiretroviral treatment (ART) is associated with improvements in food security and nutritional status, and the extent to which associations are mediated by improved physical health status (PHS).
Design
The Uganda AIDS Rural Treatment Outcomes study (UARTO), a prospective cohort of HIV-infected adults newly initiating ART in Mbarara, Uganda.
Methods
Participants initiating ART underwent quarterly structured interview and blood draws. The primary explanatory variable was time on ART, constructed as a set of binary variables for each three-month period. Outcomes were food insecurity, nutritional status and PHS. We fit multiple regression models with cluster-correlated robust estimates of variance to account for within-person dependence of observations over time, and analyses were adjusted for clinical and socio-demographic characteristics.
Results
228 ART-naive participants were followed for up to 3 years, and 41% were severely food insecure at baseline. The mean food insecurity score progressively declined (test for linear trend P<0.0001), beginning with the second quarter (b=-1.6; 95% CI, -2.7 to -0.45) and ending with the final quarter (b=-6.4; 95% CI, -10.3 to -2.5). PHS and nutritional status improved in a linear fashion over study follow-up (P<0.001). Inclusion of PHS in the regression model attenuated the relationship between ART duration and food security.
Conclusions
Among HIV-infected individuals in Uganda, food insecurity decreased and nutritional status and PHS improved over time after initiation of ART. Changes in food insecurity were partially explained by improvements in PHS. These data support early initiation of ART in resource-poor settings prior to decline in functional status to prevent worsening food insecurity and its detrimental effects on HIV treatment outcomes.
doi:10.1097/QAI.0b013e318261f064
PMCID: PMC3948100  PMID: 22692093
5.  Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection 
Retrovirology  2014;11:10.
Background
Human Endogenous Retroviruses (HERVs) comprise about 8% of the human genome and have lost their ability to replicate or to produce infectious particles after having accumulated mutations over time. We assessed the kinetics of expression of HERV-K (HML-2) Envelope mRNA transcript and surface unit (SU) and transmembrane (TM) subunit proteins during HIV-1 infection. We also mapped the specificity of the humoral response to HERV-K (HML-2) Envelope protein in HIV-1 infected subjects at different stages of disease, and correlated the response with plasma viral load.
Results
We found that HIV-1 modified HERV-K (HML-2) Env mRNA expression, resulting in the expression of a fully N-glycosylated HERV-K (HML-2) envelope protein on the cell surface. Serological mapping of HERV-K (HML-2) envelope protein linear epitopes revealed two major immunogenic domains, one on SU and another on the ectodomain of TM. The titers of HERV-K (HML-2) TM antibodies were dramatically increased in HIV-1 infected subjects (p < 0.0001). HIV-1 infected adults who control HIV-1 in the absence of therapy (“elite” controllers) had a higher titer response against TM compared to antiretroviral-treated adults (p < 0.0001) and uninfected adults (p < 0.0001).
Conclusions
These data collectively suggest that HIV-1 infection induces fully glycosylated HERV-K (HML-2) envelope TM protein to which antibodies are induced. These anti-HERV-K (HML-2) TM antibodies are a potential marker of HIV-1 infection, and are at higher titer in elite controllers. HERV-K (HML-2) envelope TM protein may be a new therapeutic target in HIV-1 infection.
doi:10.1186/1742-4690-11-10
PMCID: PMC3907665  PMID: 24472118
HIV; Antibody; HERV; Endogenous retroviruses; Transmembrane; Envelope; Elite controllers; Alternative transcripts
6.  Doppler Echocardiography Does Not Accurately Estimate Pulmonary Artery Systolic Pressure in HIV-Infected Patients 
AIDS (London, England)  2012;26(15):1967-1969.
doi:10.1097/QAD.0b013e3283579653
PMCID: PMC3897275  PMID: 22781217
HIV; pulmonary hypertension; Doppler echocardiography; right heart catheterization
7.  Composition and Function of T Cell Subpopulations Are Slow to Change Despite Effective Antiretroviral Treatment of HIV Disease 
PLoS ONE  2014;9(1):e85613.
The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4∶CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/µl (“non-controllers”, n = 42), those with undetectable viral loads on ART (“ART-suppressed”, n = 53), and HIV-uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4∶CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P<0.0001 for all comparisons). The increased ratio in ART-suppressed compared to non-controllers was driven by an increase of CD4+ T cells, with no change in the expanded CD8+ T cell population. Expansion of differentiated (CD28−CD27−CD45RA+/−CCR7−) T cell subpopulations persisted despite ART and minimal changes were noted in naïve T cell frequencies over time. Increased number of CD8+CD28− T cells and increased CD8+ CMV-specific T cell responses were associated with a decreased CD4∶CD8 ratio. Measures of T cell function demonstrated persistence of high frequencies of CD8+ T cells producing IFN–γ. Lastly, though all CD8+ subpopulations demonstrated significantly lower Ki67 expression in ART-suppressed subjects, CD4+ T cell subpopulations did not consistently show this decrease, thus demonstrating different proliferative responses in the setting of T cell depletion. In summary, this study demonstrated that CD4∶CD8 ratios remained significantly decreased and naïve T cell numbers were slow to increase despite long-term viral suppression on ART. In addition, there is a evidence of differential regulation of the CD4+ and CD8+ T cell subpopulations, suggesting independent homeostatic regulation of the two compartments.
doi:10.1371/journal.pone.0085613
PMCID: PMC3897457  PMID: 24465619
9.  Evidence for the Reliability and Validity of the Internalized AIDS-Related Stigma Scale in Rural Uganda 
AIDS and behavior  2013;17(1):427-433.
HIV infection remains highly stigmatized throughout sub-Saharan Africa despite the increasing availability of treatment. HIV-related stigma is commonly described to be highly prevalent in East Africa, but none of these studies have employed validated scales for measurement. We used data from 456 people living with HIV/AIDS in rural Uganda to validate the six-item Internalized AIDS-Related Stigma Scale. The scale demonstrated acceptable internal consistency (Cronbach’s alpha=0.73) and time stability. Exploratory factor analysis indicated the presence of a single factor. Construct validity was supported by observations that the scale was correlated with related constructs such as depression and mental health-related quality of life. The scale was able to discriminate between groups of persons who were different in terms of treatment status and their experience of HIV-related self-blame. Taken together, these findings suggest that the Internalized AIDS-Related Stigma Scale may be a useful tool for socio-behavioral HIV research.
doi:10.1007/s10461-012-0281-3
PMCID: PMC3505811  PMID: 22869104
HIV; social stigma; Uganda
10.  CD56negCD16+ NK cells are activated mature NK cells with impaired effector function during HIV-1 infection 
Retrovirology  2013;10:158.
Background
A subset of CD3negCD56negCD16+ Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations.
Results
Using CD7 as an additional NK cell marker, we found that CD3negCD56negCD16+ cells are a heterogeneous population comprised of CD7+ NK cells and CD7neg non-classical myeloid cells. CD7+CD56negCD16+ NK cells are significantly expanded in HIV-1 infection. CD7+CD56negCD16+ NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to CD7+CD56+CD16+ NK cells. CD7+CD56neg NK cells in healthy donors produced minimal IFNγ following K562 target cell or IL-12 plus IL-18 stimulation; however, they degranulated in response to K562 stimulation similar to CD7+CD56+ NK cells. HIV-1 infection resulted in reduced IFNγ secretion following K562 or cytokine stimulation by both NK cell subsets compared to healthy donors. Decreased granzyme B and perforin expression and increased expression of CD107a in the absence of stimulation, particularly in HIV-1-infected subjects, suggest that CD7+CD56negCD16+ NK cells may have recently engaged target cells. Furthermore, CD7+CD56negCD16+ NK cells have significantly increased expression of CD95, a marker of NK cell activation.
Conclusions
Taken together, CD7+CD56negCD16+ NK cells are activated, mature NK cells that may have recently engaged target cells.
doi:10.1186/1742-4690-10-158
PMCID: PMC3892122  PMID: 24351015
Natural killer cells; NK cells; CD7; Human immunodeficiency virus; HIV-1; HIV pathogenesis; CD56neg NK cells
11.  A Randomized, Controlled Trial Assessing the Effects of Raltegravir Intensification on Endothelial Function in Treated HIV Infection 
Objectives
To determine whether intensification with raltegravir improves endothelial function in antiretroviral-treated, HIV-infected individuals.
Design
Randomized, double-blinded, placebo-controlled study.
Methods
Fifty-six subjects with treatment-mediated viral suppression for at least one year were randomized to add raltegravir 400 mg twice daily or matching placebo for 24 weeks. The primary endpoint was the difference in rate of change in endothelial function (as assessed by flow-mediated vasodilation of the brachial artery [FMD]) from baseline to week 24 between the raltegravir and placebo groups. Linear mixed models were used to evaluate the association of treatment group with changes in FMD, immune activation, and measures of viral persistence.
Results
At baseline, the median CD4+ T cell count was 498 cells/mm3, nadir CD4+ T cell count was 191 cells/mm3, duration of HIV infection was 18 years, FMD was 3.3%, and hyperemic velocity (a marker of microvascular function) was 68.3 cm. There were no significant differences between treatment groups in rate of change in FMD (raltegravir group +0.032% per week, placebo group +0.023% per week; p=0.60). There were also no differences between treatment groups in rate of change in hyperemic velocity, immune activation, or viral persistence. In multivariable analysis, older age, longer duration of HIV infection, and current abacavir use were associated with lower FMD. Lower CD4+ T cell count and current abacavir use were associated with lower hyperemic velocity.
Conclusions
The addition of raltegravir to suppressive antiretroviral therapy did not have a significant impact on cardiovascular risk, as assessed by endothelial function (ClinicalTrials.gov NCT00843713).
doi:10.1097/QAI.0b013e31826e7d0f
PMCID: PMC3480968  PMID: 22918156
HIV; raltegravir intensification; endothelial function; flow-mediated vasodilation
12.  The Activity of the Integrase Inhibitor Dolutegravir Against HIV-1 Variants Isolated From Raltegravir-Treated Adults 
Background
Dolutegravir (DTG, S/GSK1349572) is an integrase inhibitor with low nanomolar potency. Susceptibility to dolutegravir and raltegravir was determined for raltegravir-resistant clinical isolates.
Methods
Genotypic and phenotypic susceptibility to integrase inhibitors was examined using 39 clinical isolate samples obtained from 18 adults who had exhibited incomplete viral suppression on a raltegravir-based regimen.
Results
Of 39 samples evaluated, 30 had genotypic and phenotypic resistance to raltegravir. All samples lacking raltegravir resistance retained complete susceptibility to dolutegravir. Of the 30 samples with genotypic evidence of raltegravir resistance, the median level of phenotypic resistance to raltegravir was high (median fold change in inhibitory concentration at 50%, >81; range, 3.7 to >87) while the level of resistance to dolutegravir was close to that of wild-type variants (median fold change, 1.5; range, 0.9–19.0). Longitudinal samples from 5 subjects collected during long-term failure of raltegravir revealed time-dependent general decreases in phenotypic susceptibility to raltegravir, with minimal changes in phenotypic susceptibility to dolutegravir. The median fold change to dolutegravir for isolates containing changes at G140S + Q148H; G140S + Q148R; T97A + Y143R; and N155H (thus including raltegravir signature resistance codons) were 3.75, 13.3, 1.05, and 1.37, respectively.
Conclusions
Dolutegravir retained in vitro activity against clinical isolates obtained from subjects who failed raltegravir-based therapy at near wild-type levels for variants containing the Y143 and N155 resistance mutations. Isolates with Q148 plus additional integrase mutations possessed a broader range of and more reduced susceptibility to dolutegravir.
doi:10.1097/QAI.0b013e31826bfd02
PMCID: PMC3804312  PMID: 22878423
Dolutegravir; DTG; S/GSK1349572; integrase inhibitor; raltegravir resistance; UCSF SCOPE cohort
13.  Prospective Antiretroviral Treatment of Asymptomatic, HIV-1 Infected Controllers 
PLoS Pathogens  2013;9(10):e1003691.
The study of HIV-infected “controllers” who are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART) may provide insights for HIV cure and vaccine strategies. Despite maintaining very low levels of plasma viremia, controllers have elevated immune activation and accelerated atherosclerosis. However, the degree to which low-level replication contributes to these phenomena is not known. Sixteen asymptomatic controllers were prospectively treated with ART for 24 weeks. Controllers had a statistically significant decrease in ultrasensitive plasma and rectal HIV RNA levels with ART. Markers of T cell activation/dysfunction in blood and gut mucosa also decreased substantially with ART. Similar reductions were observed in the subset of “elite” controllers with pre-ART plasma HIV RNA levels below conventional assays (<40 copies/mL). These data confirm that HIV replication persists in controllers and contributes to a chronic inflammatory state. ART should be considered for these individuals (ClinicalTrials.gov NCT01025427).
Author Summary
HIV-infected “controllers” are rare individuals who are HIV-seropositive but are able to maintain low levels of plasma HIV RNA in the absence of antiretroviral therapy (ART). There has been intense interest in characterizing these unique individuals because they have been considered as a potential model for a “functional cure” of HIV. Previously, our group has shown that controllers have elevated levels of T cell activation and accelerated atherosclerosis, suggesting that very low levels of viral replication may lead to disproportionately high levels of immune activation. However, the degree to which viral replication contributes to these outcomes is not known. We therefore conducted the first, prospective study of ART initiation in a cohort of asymptomatic HIV-infected controllers, in order to determine the virologic and immunologic effects of treating controllers with ART. Controllers had a significant decreases in ultrasensitive plasma HIV RNA, rectal HIV RNA, and markers of T cell activation/dysfunction in blood and gut mucosa with ART. Similar reductions were observed in the subset of “elite” controllers with extremely low pre-ART plasma HIV RNA levels (<40 copies/mL). These data suggest that HIV replication persists in controllers and contributes to a chronic inflammatory state.
doi:10.1371/journal.ppat.1003691
PMCID: PMC3795031  PMID: 24130489
15.  GPS-measured distance to clinic, but not self-reported transportation factors, are associated with missed HIV clinic visits in rural Uganda 
AIDS (London, England)  2013;27(9):1503-1508.
Objective
Studies of the association between transportation barriers and HIV-related health outcomes have shown both positive and negative effects, possibly because a reliable, validated measure of transportation barriers has not been identified.
Design
Prospective cohort study of HIV-infected patients in rural Uganda.
Methods
Participants were enrolled from the HIV clinic at the regional referral hospital in Mbarara, Uganda as part of the Uganda AIDS Rural Treatment Outcomes (UARTO) Study. We collected the following measures of transportation barriers to HIV clinic: global positioning systems (GPS)-tracked distance measured by driving participants to their homes along their typical route; straight-line GPS distance from clinic to home, calculated with the Great Circle Formula; self-reported travel time; and self-reported travel cost. We assessed inter-measure agreement using linear regression, correlation coefficients and κ statistics (by measure quartile) and validated measures by fitting linear regression models to estimate associations with days late for clinic visits.
Results
One hundred and eighty-eight participants were tracked with GPS. Seventy-six percent were women, with a median age of 40 years and median CD4 cell count of 193 cells/μl. We found a high correlation between GPS-based distance measures (β = 0.74, P < 0.001, R2 = 0.92, k = 0.73), but little correlation between GPS-based and self-reported measures (all R2 ≤ 0.4). GPS-based measures were associated with days late to clinic (P < 0.001); but neither self-reported measure was associated (P > 0.85).
Conclusion
GPS-measured distance to clinic is associated with HIV clinic absenteeism and should be prioritized over self-reported measures to optimally risk-stratify patients accessing care in rural, resource-limited settings.
doi:10.1097/QAD.0b013e32835fd873
PMCID: PMC3745818  PMID: 23435294
distance to clinic; global positioning systems; HIV/AIDS; linkage to care; sub-Saharan Africa; transportation; Uganda
16.  Altered distribution of mucosal NK cells during HIV infection 
Mucosal immunology  2011;5(1):30-40.
The human gut mucosa is a major site of HIV infection and infection-associated pathogenesis. Increasing evidence shows that natural killer (NK) cells play an important role in control of HIV infection but the mechanism(s) by which they mediate antiviral activity in the gut is unclear. Here we show two distinct subsets of NK cells exist in the gut, one localized to intraepithelial spaces (IEL) and the other to the lamina propria (LP). The frequency of both subsets of NK cells was reduced in chronic infection, whereas IEL NK cells remained stable in spontaneous controllers with protective KIR/HLA genotypes. Both IEL and LP NK cells were significantly expanded in immunologic non-responsive (INR) patients, who incompletely recovered CD4+ T cells on HAART. These data suggest that both IEL and LP NK cells may expand in the gut in an effort to compensate for compromised CD4+ T cell recovery, but that only IEL NK cells may be involved in providing durable control of HIV in the gut,
doi:10.1038/mi.2011.40
PMCID: PMC3740353  PMID: 21993602
17.  Gag-Positive Reservoir Cells Are Susceptible to HIV-Specific Cytotoxic T Lymphocyte Mediated Clearance In Vitro and Can Be Detected In Vivo 
PLoS ONE  2013;8(8):e71879.
Resting CD4+ T cells infected with HIV persist in the presence of suppressive anti-viral therapy (ART) and are barriers to a cure. One potential curative approach, therapeutic vaccination, is fueled by recognition of the ability of a subset of elite controllers (EC) to control virus without therapy due to robust anti-HIV immune responses. Controllers have low levels of integrated HIV DNA and low levels of replication competent virus, suggesting a small reservoir. As our recent data indicates some reservoir cells can produce HIV proteins (termed GPR cells for Gag-positive reservoir cells), we hypothesized that a fraction of HIV-expressing resting CD4+ T cells could be efficiently targeted and cleared in individuals who control HIV via anti-HIV cytotoxic T lymphocytes (CTL). To test this we examined if superinfected resting CD4+ T cells from EC express HIV Gag without producing infectious virus and the susceptibility of these cells to CTL. We found that resting CD4+ T cells expressed HIV Gag and were cleared by autologous CD8+ T cells from EC. Importantly, we found the extent of CTL clearance in our in vitro assay correlates with in vivo reservoir size and that a population of Gag expressing resting CD4+ T cells exists in vivo in patients well controlled on therapy.
doi:10.1371/journal.pone.0071879
PMCID: PMC3737195  PMID: 23951263
18.  Food Insecurity, Depression and the Modifying Role of Social Support among People Living with HIV/AIDS in Rural Uganda 
Social science & medicine (1982)  2012;74(12):2012-2019.
Depression is common among people living with HIV/AIDS and contributes to a wide range of worsened HIV-related outcomes, including AIDS-related mortality. Targeting modifiable causes of depression, either through primary or secondary prevention, may reduce suffering as well as improve HIV-related outcomes. Food insecurity is a pervasive source of uncertainty for those living in resource-limited settings, and cross-sectional studies have increasingly recognized it as a critical determinant of poor mental health. Using cohort data from 456 men and women living with HIV/AIDS initiating HIV antiretroviral therapy in rural Uganda, we sought to (a) estimate the association between food insecurity and depression symptom severity, (b) assess the extent to which social support may serve as a buffer against the adverse effects of food insecurity, and (c) determine whether the buffering effects are specific to certain types of social support. Quarterly data were collected by structured interviews and blood draws. The primary outcome was depression symptom severity, measured by a modified Hopkins Symptom Checklist for Depression. The primary explanatory variables were food insecurity, measured with the Household Food Insecurity Access Scale, and social support, measured with a modified version of the Functional Social Support Questionnaire. We found that food insecurity was associated with depression symptom severity among women but not men, and that social support buffered the impacts of food insecurity on depression. We also found that instrumental support had a greater buffering influence than emotional social support. Interventions aimed at improving food security and strengthening instrumental social support may have synergistic beneficial effects on both mental health and HIV outcomes among PLWHA in resource-limited settings.
doi:10.1016/j.socscimed.2012.02.033
PMCID: PMC3348339  PMID: 22513248
AIDS/HIV; international health; social support; food; food insecurity; depression; Uganda
19.  T Cells Target APOBEC3 Proteins in Human Immunodeficiency Virus Type 1-Infected Humans and Simian Immunodeficiency Virus-Infected Indian Rhesus Macaques 
Journal of Virology  2013;87(11):6073-6080.
APOBEC3 proteins mediate potent antiretroviral activity by hypermutating the retroviral genome during reverse transcription. To counteract APOBEC3 and gain a replicative advantage, lentiviruses such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) have evolved the Vif protein, which targets APOBEC3 proteins for proteasomal degradation. However, the proteasome plays a critical role in the generation of T cell peptide epitopes. Whether Vif-mediated destruction of APOBEC3 proteins leads to the generation and presentation of APOBEC3-derived T cell epitopes on the surfaces of lentivirus-infected cells remains unknown. Here, using peptides derived from multiple Vif-sensitive APOBEC3 proteins, we identified APOBEC3-specific T cell responses in both HIV-1-infected patients and SIV-infected rhesus macaques. These results raise the possibility that these T cell responses may be part of the larger antiretroviral immune response.
doi:10.1128/JVI.00579-12
PMCID: PMC3648095  PMID: 23536679
20.  Awareness of Kaposi’s Sarcoma-associated Herpesvirus among Men who Have Sex with Men 
Sexually transmitted diseases  2008;35(12):1011-1014.
Background
Despite burgeoning scientific knowledge about Kaposi’s sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi’s sarcoma (KS), little is known about awareness of this virus in the general community. This is particularly the case for men who have sex with men (MSM), the group at greatest risk for infection.
Methods
The California Health Interview Survey was a random digit-dial survey of over 50,000 households. Men age 18–64 years who self-identified as gay or bisexual were subsequently re-contacted for a follow-up study of HIV-related knowledge and behavior in which they were asked if they had heard of KS and to describe the cause of KS.
Results
Of 398 MSM interviewed, 73.0% (95% CI: 65.0% to 79.7%) had heard of KS. However, only 6.4% (95% CI: 4.4% to 9.2%) of participants correctly identified that KS is caused by KSHV or a virus other than HIV. Postgraduate education, urban residence, and concurrent HIV infection were all independently associated with greater awareness of the viral origin of KS.
Conclusion
Awareness of KSHV is very low overall among MSM and only somewhat higher, but still unacceptably low, among HIV-infected MSM. Significant efforts are needed to increase awareness of KSHV as a sexually transmitted infection in this subpopulation
doi:10.1097/OLQ.0b013e318182c91f
PMCID: PMC2593118  PMID: 18665016
men who have sex with men; homosexuality; male; Kaposi sarcoma; herpesvirus 8; human; herpesvirus; Kaposi’s sarcoma-associated; sampling studies
21.  A Causal Framework for Understanding the Effect of Losses to Follow-up on Epidemiologic Analyses in Clinic-based Cohorts: The Case of HIV-infected Patients on Antiretroviral Therapy in Africa 
American Journal of Epidemiology  2012;175(10):1080-1087.
Although clinic-based cohorts are most representative of the “real world,” they are susceptible to loss to follow-up. Strategies for managing the impact of loss to follow-up are therefore needed to maximize the value of studies conducted in these cohorts. The authors evaluated adult patients starting antiretroviral therapy at an HIV/AIDS clinic in Uganda, where 29% of patients were lost to follow-up after 2 years (January 1, 2004–September 30, 2007). Unweighted, inverse probability of censoring weighted (IPCW), and sampling-based approaches (using supplemental data from a sample of lost patients subsequently tracked in the community) were used to identify the predictive value of sex on mortality. Directed acyclic graphs (DAGs) were used to explore the structural basis for bias in each approach. Among 3,628 patients, unweighted and IPCW analyses found men to have higher mortality than women, whereas the sampling-based approach did not. DAGs encoding knowledge about the data-generating process, including the fact that death is a cause of being classified as lost to follow-up in this setting, revealed “collider” bias in the unweighted and IPCW approaches. In a clinic-based cohort in Africa, unweighted and IPCW approaches—which rely on the “missing at random” assumption—yielded biased estimates. A sampling-based approach can in general strengthen epidemiologic analyses conducted in many clinic-based cohorts, including those examining other diseases.
doi:10.1093/aje/kwr444
PMCID: PMC3353135  PMID: 22306557
Africa; antiretroviral therapy; clinic-based cohorts; directed acyclic graphs; informative censoring; inverse probability of censoring weights; loss to follow-up; missing at random
22.  Prevalence and Significance of HIV-1 Drug Resistance Mutations among Patients on Antiretroviral Therapy with Detectable Low-Level Viremia 
Antimicrobial Agents and Chemotherapy  2012;56(11):5998-6000.
HIV-1 resistance testing was performed in 47 antiretroviral (ARV)-treated subjects with low-level viremia (LLV) of <1,000 copies/ml. The median viral load was 267 copies/ml. In those with ≥2 LLV episodes, 44% accumulated additional resistance mutations. Fewer active ARVs and longer elapsed time were associated with an increased risk of resistance accumulation after controlling for adherence and viral load. Virologic failure followed 16% of LLV time points. Strategies for early intervention after LLV episodes should be further studied.
doi:10.1128/AAC.01217-12
PMCID: PMC3486544  PMID: 22890763
23.  HIV Infection Is Associated With Decreased Thrombin Generation 
HIV infection is associated with decreased thrombin generation and an increased antithrombin level. These data suggest that HIV infection may not be associated with an increased propensity towards clotting.
Background. Excess risk of cardiovascular disease occurs in effectively treated individuals with human immunodeficiency virus (HIV) infection. Although elevated plasma D-dimer levels are associated with increased morbidity and mortality, the impact of HIV infection on coagulation in vivo has not been well studied.
Methods. We measured D-dimers, antithrombin, endogenous thrombin potential (ETP; a functional measure of thrombin generation in vitro), thrombin/antithrombin complexes (TAT; a measure of thrombin generation in vivo), tissue factor, prothrombin fragment 1 + 2 (F1+2), and normalized APC sensitivity ratio (nAPCsr) in 199 HIV-positive men who were receiving antiretroviral therapy and had an undetectable HIV RNA level, in 79 HIV-positive untreated men, and in 39 uninfected controls.
Results. Median antithrombin levels were higher while the ETP was lower among HIV-infected adults (treated and untreated), compared with controls. There were few differences between coagulation markers in the 2 HIV groups. Compared with controls, the nAPCsr was lower in treated men and the TAT level was lower in untreated individuals. We observed little difference among measured levels of D-dimer, tissue factor, or F1+2 between HIV-infected individuals and controls. Antiretroviral therapy exposure was associated with a lower antithrombin level, a lower nAPCsr, and a lower ETP, while history of opportunistic infection was associated with a higher nAPCsr.
Conclusions. HIV infection is associated with decreased thrombin generation, as measured by the ETP, and an increased antithrombin level. These data suggest that HIV infection may not be associated with increased propensity toward clotting, as has been suggested on the basis of isolated measures of D-dimer levels.
doi:10.1093/cid/cis014
PMCID: PMC3309887  PMID: 22438347
24.  Understanding Reasons for and Outcomes of Patients Lost to Follow-Up in Antiretroviral Therapy Programs in Africa Through a Sampling-Based Approach 
Objectives
Losses to follow-up after initiation of antiretroviral therapy (ART) are common in Africa and are a considerable obstacle to understanding the effectiveness of nascent treatment programs. We sought to characterize, through a sampling-based approach, reasons for and outcomes of patients who become lost to follow-up.
Design
Cohort study.
Methods
We searched for and interviewed a representative sample of lost patients or close informants in the community to determine reasons for and outcomes among lost patients.
Results
Three thousand six hundred twenty-eight HIV-infected adults initiated ART between January 1, 2004 and September 30, 2007 in Mbarara, Uganda. Eight hundred twenty-nine became lost to follow-up (cumulative incidence at 1, 2, and 3 years of 16%, 30%, and 39%). We sought a representative sample of 128 lost patients in the community and ascertained vital status in 111 (87%). Top reasons for loss included lack of transportation or money and work/child care responsibilities. Among the 111 lost patients who had their vital status ascertained through tracking, 32 deaths occurred (cumulative 1-year incidence 36%); mortality was highest shortly after the last clinic visit. Lower pre-ART CD4+ T-cell count, older age, low blood pressure, and a central nervous system syndrome at the last clinic visit predicted deaths. Of patients directly interviewed, 83% were in care at another clinic and 71% were still using ART.
Conclusions
Sociostructural factors are the primary reasons for loss to follow-up. Outcomes among the lost are heterogeneous: both deaths and transfers to other clinics were common. Tracking a sample of lost patients is an efficient means for programs to understand site-specific reasons for and outcomes among patients lost to follow-up.
doi:10.1097/QAI.0b013e3181b843f0
PMCID: PMC3606953  PMID: 19745753
Africa; antiretroviral scale-up; losses to follow-up; monitoring and evaluation; sampling studies
25.  Food insecurity is associated with morbidity and patterns of healthcare utilization among HIV-infected individuals in a resource-poor setting 
AIDS (London, England)  2012;26(1):67-75.
Objective
We undertook a longitudinal study in rural Uganda to understand the association of food insecurity with morbidity and patterns of healthcare utilization among HIV-infected individuals enrolled in an antiretroviral therapy program.
Design
Longitudinal cohort study.
Methods
Participants were enrolled from the Uganda AIDS Rural Treatment Outcomes cohort, and underwent quarterly structured interviews and blood draws. The primary predictor was food insecurity measured by the validated Household Food Insecurity Access Scale. Primary outcomes included health-related quality of life measured by the validated Medical Outcomes Study-HIV Physical Health Summary (PHS), incident self-reported opportunistic infections, number of hospitalizations, and missed clinic visits. To estimate model parameters, we used the method of generalized estimating equations, adjusting for sociodemographic and clinical variables. Explanatory variables were lagged by 3 months to strengthen causal interpretations.
Results
Beginning in May 2007, 458 persons were followed for a median of 2.07 years, and 40% were severely food insecure at baseline. Severe food insecurity was associated with worse PHS, opportunistic infections, and increased hospitalizations (results were similar in concurrent and lagged models). Mild/moderate food insecurity was associated with missed clinic visits in concurrent models, whereas in lagged models, severe food insecurity was associated with reduced odds of missed clinic visits.
Conclusion
Based on the negative impact of food insecurity on morbidity and patterns of healthcare utilization among HIV-infected individuals, policies and programs that address food insecurity should be a critical component of HIV treatment programs worldwide.
doi:10.1097/QAD.0b013e32834cad37
PMCID: PMC3606954  PMID: 21904186
AIDS; food insecurity; healthcare utilization; HIV; morbidity; Uganda

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