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1.  Legionnaires’ Disease in South Africa, 2012–2014 
Emerging Infectious Diseases  2016;22(1):131-133.
During June 2012–September 2014, we tested patients with severe respiratory illness for Legionella spp. infection and conducted a retrospective epidemiologic investigation. Of 1,805 patients tested, Legionella was detected in samples of 21 (1.2%); most were adults who had HIV or tuberculosis infections and were inappropriately treated for Legionella.
PMCID: PMC4696697  PMID: 26692504
Legionella spp.; Legionnaires’ disease; pneumonia; South Africa; Legionellosis; legionella; bacteria; respiratory infections
2.  Assessing the impact of pneumococcal conjugate vaccines on invasive pneumococcal disease using polymerase chain reaction-based surveillance: an experience from South Africa 
BMC Infectious Diseases  2015;15:450.
The use of molecular diagnostic techniques for the evaluation of the impact of pneumococcal conjugate vaccines (PCVs) has not been documented. We aimed to evaluate the impact of PCVs on invasive pneumococcal disease (IPD) using polymerase chain reaction (PCR)-based techniques and compare with results obtained from culture-based methods.
We implemented two independent surveillance programs for IPD among individuals hospitalized at one large surveillance site in Soweto, South Africa during 2009–2012: (i) PCR-based (targeting the lytA gene) syndromic pneumonia surveillance; and (ii) culture-based laboratory surveillance. Positive samples were serotyped. The molecular serotyping assay included targets for 42 serotypes including all serotypes/serogroups included in the 7-valent (PCV-7) and 13-valent (PCV-13) PCV. The Quellung reaction was used for serotyping of culture-positive cases. We calculated the change in rates of IPD (lytA- or culture-positive) among HIV-uninfected children aged <2 years from the year of PCV-7 introduction (2009) to the post-vaccine years (2011 or 2012).
During the study period there were 607 lytA-positive and 1,197 culture-positive cases that were serotyped. Samples with lytA cycle threshold (Ct)-values ≥35 (30.2 %; 123/407) were significantly less likely to have a serotype/serogroup detected for serotypes included in the molecular serotyping assay than those with Ct-values <35 (78.0 %; 156/200) (p < 0.001). From 2009 to 2012 rates of PCV-7 serotypes/serogroups decreased −63.8 % (95 % CI: −79.3 % to −39.1 %) among lytA-positive cases and −91.7 % (95 % CI: −98.8 % to −73.6 %) among culture-positive cases. Rates of lytA-positive non-vaccine serotypes/serogroups also significantly decreased (−71.7 %; 95 % CI: −81.1 % to −58.5 %) over the same period. Such decline was not observed among the culture-positive non-vaccine serotypes (1.2 %; 95 % CI: −96.7 % to 58.4 %).
Significant downward trends in IPD PCV-7 serotype-associated rates were observed among patients tested by PCR or culture methods; however trends of non-vaccine serotypes/serogroups differed between the two groups. Misclassifications of serotypes/serogroups, affecting the use of non-vaccine serotypes as a control group, may have occurred due to the low performance of the serotyping assay among lytA-positive cases with high Ct-values. Until PCR methods improve further, culture methods should continue to be used to monitor the effects of PCV vaccination programs on IPD incidence.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-1198-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4620746  PMID: 26496761
Pneumococcus; Conjugate vaccine; lytA; Molecular serotyping; South Africa
3.  Parainfluenza Virus Infection Among Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Children and Adults Hospitalized for Severe Acute Respiratory Illness in South Africa, 2009–2014 
Open Forum Infectious Diseases  2015;2(4):ofv139.
Parainfluenza is associated with a significant amount of severe respiratory disease in South Africa, especially among children <5 years of age and individuals that are HIV-infected.
Background. Parainfluenza virus (PIV) is a common cause of acute respiratory tract infections, but little is known about PIV infection in children and adults in Africa, especially in settings where human immunodeficiency virus (HIV) prevalence is high.
Methods. We conducted active, prospective sentinel surveillance for children and adults hospitalized with severe acute respiratory illness (SARI) from 2009 to 2014 in South Africa. We enrolled controls (outpatients without febrile or respiratory illness) to calculate the attributable fraction for PIV infection. Respiratory specimens were tested by multiplex real-time reverse-transcription polymerase chain reaction assay for parainfluenza types 1, 2, and 3.
Results. Of 18 282 SARI cases enrolled, 1188 (6.5%) tested positive for any PIV type: 230 (19.4%) were type 1; 168 (14.1%) were type 2; 762 (64.1%) were type 3; and 28 (2.4%) had coinfection with 2 PIV types. After adjusting for age, HIV serostatus, and respiratory viral coinfection, the attributable fraction for PIV was 65.6% (95% CI [confidence interval], 47.1–77.7); PIV contributed to SARI among HIV-infected and -uninfected children <5 years of age and among individuals infected with PIV types 1 and 3. The observed overall incidence of PIV-associated SARI was 38 (95% CI, 36–39) cases per 100 000 population and was highest in children <1 year of age (925 [95% CI, 864–989] cases per 100 000 population). Compared with persons without HIV, persons with HIV had an increased relative risk of PIV hospitalization (9.4; 95% CI, 8.5–10.3).
Conclusions. Parainfluenza virus causes substantial severe respiratory disease in South Africa among children <5 years of age, especially those that are infected with HIV.
PMCID: PMC4630450  PMID: 26566534
HIV; parainfluenza virus; severe acute respiratory illness; South Africa
4.  Evaluation of influenza vaccine effectiveness and description of circulating strains in outpatient settings in South Africa, 2014 
The effectiveness of the trivalent seasonal influenza vaccine during the 2014 season in South Africa was assessed using a test-negative case–control study design including 472 cases and 362 controls. Influenza A(H3N2) was the dominant strain circulating. The overall vaccine effectiveness estimate, adjusted for age and underlying conditions, was 43·1% (95% CI: −26·8–74·5). 2014 H3N2 viruses from South Africa were mainly in sublineage 3C.3 with accumulation of amino acid changes that differentiate them from the vaccine strain in 3C.1.
PMCID: PMC4474497  PMID: 25865249
Effectiveness; influenza; vaccine
5.  Genetic diversity and molecular epidemiology of human rhinoviruses in South Africa 
Rhinoviruses (RV) are a well-established cause of respiratory illness. RV-C has been associated with more severe illness. We aimed to characterize and compare the clinical presentations and disease severity of different RV type circulating in South Africa.
We performed two analyses of RV-positive specimens identified through surveillance in South Africa across all age groups. First, RV-positive specimens identified through severe acute respiratory illness (SARI) surveillance in four provinces was randomly selected from 2009 to 2010 for molecular characterization. Second, RV-positive specimens identified through SARI, influenza-like illness (ILI) and control surveillance at hospitals and outpatient clinics in during 2012–2013 were used to determine the association of RV type with severe disease. Selected specimens were sequenced, and phylogenetic analysis was performed.
Among the 599 sequenced specimens from 2009 to 2010 and 2012 to 2013, RV-A (285, 48%) and RV-C (247, 41%) were more commonly identified than RV-B (67, 11%), with no seasonality and a high genetic diversity. A higher prevalence of RV infection was identified in cases with SARI [515/962 (26%); aRRR = 1·6; 95% CI 1·21; 2·2] and ILI [356/962 (28%); aRRR = 1·9; 95% CI 1·37; 2·6] compared with asymptomatic controls (91/962, 22%). There was no difference in disease severity between the different type when comparing SARI, ILI and controls.
All three type of RV were identified in South Africa, although RV-A and RV-C were more common than RV-B. RV was associated with symptomatic respiratory illness; however, there was no association between RV type and disease severity.
PMCID: PMC4181821  PMID: 24990601
Disease association; genetic diversity; rhinovirus; South Africa
6.  Epidemiology of Influenza Virus Types and Subtypes in South Africa, 2009–20121 
Emerging Infectious Diseases  2014;20(7):1149-1156.
Patient age and co-infections, but not disease severity, were associated with virus type and subtype.
To determine clinical and epidemiologic differences between influenza caused by different virus types and subtypes, we identified patients and tested specimens. Patients were children and adults hospitalized with confirmed influenza and severe acute respiratory illness (SARI) identified through active, prospective, hospital-based surveillance from 2009–2012 in South Africa. Respiratory specimens were tested, typed, and subtyped for influenza virus by PCR. Of 16,005 SARI patients tested, 1,239 (8%) were positive for influenza virus. Patient age and co-infections varied according to virus type and subtype, but disease severity did not. Case-patients with influenza B were more likely than patients with influenza A to be HIV infected. A higher proportion of case-patients infected during the first wave of the 2009 influenza pandemic were 5–24 years of age (19%) than were patients infected during the second wave (9%). Although clinical differences exist, treatment recommendations do not differ according to subtype; prevention through vaccination is recommended.
PMCID: PMC4073865  PMID: 24960314
influenza; influenza A; influenza B; H3N2; H1N1; types; subtypes; pneumonia; South Africa; viruses
7.  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.
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.
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.
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.
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.
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.
PMCID: PMC3720865  PMID: 23370465
HIV-1; Africa; genome; acute infection; cytotoxic T-lymphocytes; progression
8.  Comparison of Viral Env Proteins from Acute and Chronic Infections with Subtype C Human Immunodeficiency Virus Type 1 Identifies Differences in Glycosylation and CCR5 Utilization and Suggests a New Strategy for Immunogen Design 
Journal of Virology  2013;87(13):7218-7233.
Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine. We compared phenotypic and genetic variation in HIV-1 env genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission. We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell. We confirmed an earlier observation that the transmitted viruses were, on average, modestly underglycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event. We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies. We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of env, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.
PMCID: PMC3700278  PMID: 23616655
9.  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.
PMCID: PMC3415934  PMID: 22551813
10.  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.
PMCID: PMC3466366  PMID: 22966086
11.  Vertical T cell immunodominance and epitope entropy determine HIV-1 escape 
HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.
PMCID: PMC3533301  PMID: 23221345
12.  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.
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.
PMCID: PMC3206740  PMID: 21198409
13.  Conserved positive selection signals in gp41 across multiple subtypes and difference in selection signals detectable in gp41 sequences sampled during acute and chronic HIV-1 subtype C infection 
Virology Journal  2008;5:141.
The high diversity of HIV variants driving the global AIDS epidemic has caused many to doubt whether an effective vaccine against the virus is possible. However, by identifying the selective forces that are driving the ongoing diversification of HIV and characterising their genetic consequences, it may be possible to design vaccines that pre-empt some of the virus' more common evasion tactics. One component of such vaccines might be the envelope protein, gp41. Besides being targeted by both the humoral and cellular arms of the immune system this protein mediates fusion between viral and target cell membranes and is likely to be a primary determinant of HIV transmissibility.
Using recombination aware analysis tools we compared site specific signals of selection in gp41 sequences from different HIV-1 M subtypes and circulating recombinant forms and identified twelve sites evolving under positive selection across multiple major HIV-1 lineages. To identify evidence of selection operating during transmission our analysis included two matched datasets sampled from patients with acute or chronic subtype C infections. We identified six gp41 sites apparently evolving under different selection pressures during acute and chronic HIV-1 infections. These sites mostly fell within functional gp41 domains, with one site located within the epitope recognised by the broadly neutralizing antibody, 4E10.
Whereas these six sites are potentially determinants of fitness and are therefore good candidate targets for subtype-C specific vaccines, the twelve sites evolving under diversifying selection across multiple subtypes might make good candidate targets for broadly protective vaccines.
PMCID: PMC2630941  PMID: 19025632
14.  Transmission of HIV-1 CTL Escape Variants Provides HLA-Mismatched Recipients with a Survival Advantage 
PLoS Pathogens  2008;4(3):e1000033.
One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is associated with lower viral load and higher CD4+ counts.
Author Summary
Following infection with HIV, it is well established that a person's genetic makeup is a major determinant of how quickly they will progress to AIDS. Particularly important is the class I Human leukocyte antigen (HLA) gene that is responsible for alerting the immune system to HIV's presence. One of the reasons our immune systems are unable to beat HIV is that the virus can mutate to forms that our HLA genes no longer recognise. However, some people have versions of the HLA gene (for example HLA-B*57 and HLA-B*5801) that are known to force HIV to tolerate mutations that damage its ability to reproduce. Slower HIV reproduction is thought to be one reason that HLA-B*57 and HLA-B*5801 positive people progress to AIDS more slowly than most other HIV infected persons. We report here on a study of HLA-B*57 and HLA-B*5801 negative women in which better control of disease tended to be associated with their being infected with viruses carrying mutations that have been previously shown to reduce replication. These mutations characterise viruses found infecting HLA-B*57 and HLA-B*5801 positive people. This indicates for the first time that HLA-B*57 or HLA-B*5801 negative people that are infected by such reproductively compromised viruses may also experience better survival prospects.
PMCID: PMC2265427  PMID: 18369479

Results 1-14 (14)