[Show abstract][Hide abstract] ABSTRACT: To investigate whether distinct populations have differing HIV-1 neutralizing antibody responses, we compared 20 women from Tanzania's HISIS cohort infected with multiple subtypes and 22 women from South Africa's exclusively subtype C CAPRISA cohort. By two years post infection, 35% in HISIS developed neutralization breadth compared to 9% in CAPRISA (p=0.0131). Cumulative viral loads between 3 and 12 months were higher in HISIS (p=0.046) and strongly associated with breadth (p<0.0001). While viral load was the strongest predictor, other factors may play a role as the odds of developing breadth remained higher in HISIS even after correction for viral load.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: While antiretroviral pre-exposure prophylaxis (PrEP) prevents HIV acquisition, it is not known if it alters HIV disease progression. This study assesses whether tenofovir gel impacted on disease progression among CAPRISA 004 microbicide trial seroconvertors.
METHODS: Eighty-three seroconvertors from the tenofovir and placebo gel arms of the CAPRISA 004 trial were monitored prospectively for a minimum two years by CD4 count and viral load (VL). Linear mixed models were fitted to HIV VL, and log rank test was used to compare time to reach CD4<350.
RESULTS: Median 2-week post-infection VL was 4.74 and 4.45 log copies/ml in women assigned to tenofovir gel (n=32) and placebo gel (n=51) (p=0.189). Corresponding 12-month post-infection VLs were 4.24 and 3.70 log copies/ml (p=0.016). After adjusting for clinical and behavioral characteristics and protective HLA alleles, mean VLs within the first two years were 4.51 and 4.02 log copies/ml in women from the tenofovir and placebo arms (p=0.013). Among women with vaginal tenofovir measurements, mean VL were 4.53 and 4.60 log copies/ml in those with detectable versus undetectable levels (p=0.840). Overall mean CD4 counts were 463 and 514 cells/µl in women assigned to tenofovir and placebo (p=0.290). Thirty-two (38.6%) women reached CD4<350 at median 9.4 months post-infection, 13 (40.6%) from the tenofovir and 19 (37.3%) from the placebo arms (p=0.786).
CONCLUSIONS: Tenofovir gel had no impact on post-infection CD4 counts or the rate of CD4 decline. While seroconvertors from the tenofovir arm experienced higher VLs, this did not result in a need for earlier antiretroviral therapy.
Journal of acquired immune deficiency syndromes (1999). 09/2014;
[Show abstract][Hide abstract] ABSTRACT: Neutralizing antibodies (nAbs) are a high priority for vaccines that aim to prevent the acquisition of HIV-1 infection. Vaccine effectiveness will depend on the extent to which induced antibodies neutralize the global diversity of circulating HIV-1 variants. Using large panels of genetically and geographically diverse HIV-1 Env-pseudotyped viruses and chronic infection plasma samples, we unambiguously show that cross-clade nAb responses are commonly induced in response to infection by any virus clade. Nonetheless, neutralization was significantly greater when the plasma clade matched the clade of the virus being tested. This within-clade advantage was diminished in older, more diverse epidemics in southern Africa, the US and Europe compared to more recent epidemics in Asia. It was most pronounced for circulating recombinant form (CRF) 07_BC, which is common in China and is the least divergent lineage studied; this was followed by the slightly more diverse Asian CRF01_AE. We found no evidence that transmitted/founder viruses are generally more susceptible to neutralization and are therefore easier targets for vaccination than chronic viruses. Features of the gp120 V1V2 loop, in particular length, net charge and number of N-linked glycans, were associated with Env susceptibility and plasma neutralization potency in a manner consistent with neutralization-escape being a force that drives viral diversification and plasma neutralization breadth. The overall susceptibility of Envs and potencies of plasmas were highly predictive of the neutralization outcome of any single virus/plasma combination. These findings highlight important considerations for the design and testing of candidate HIV-1 vaccines that aim to elicit effective nAbs.
[Show abstract][Hide abstract] ABSTRACT: Sexually transmitted infections (STI) and bacterial vaginosis (BV) cause female genital tract inflammation. This inflammation, which is often present in the absence of symptoms, is associated with increased susceptibility to HIV infection. We aimed to evaluate genital cytokine profiles and the degree of inflammation associated with common STIs and BV.
[Show abstract][Hide abstract] ABSTRACT: In South Africa, adolescents constitute a key population at high risk of HIV acquisition. However, little is known about HIV transmission among students within schools. This study was undertaken to assess the risk factors for HIV infection and the extent of transmission among rural high school students. Between February and May 2012, consenting students from five randomly selected public sector high schools in rural KwaZulu-Natal participated in an anonymized cross-sectional survey. Dried blood spot samples were collected and tested for HIV. βHCG levels were measured in females for pregnancy. Family circumstances, socio-demographic and behavioral factors were assessed as potential risk factors. A subset (106/148, 72%) of HIV positive samples underwent gag p17p24 sequencing for phylogenetic analysis. A total of 3242 students (81.7% of enrolled students) participated. HIV prevalence was 6.8% [95% Confidence Interval (CI) 3.9-9.8%] in girls and 2.7% (CI 1.6-3.8%) in boys (aOR=3.0, CI 2.4-3.8; p<0.001). HIV prevalence increased from 4.6% (95% CI 1.9-7.3) in the 12-15 year old girls to 23.1% (95% CI 7.7-38.5) in girls over 20 years, whilst in boys HIV prevalence increased from 2.7% (95% CI 0.6-4.9) in the 12-15 year olds to 11.1% (95% CI 2.7-19.4) in those over 20 years. Sequencing of samples obtained from students revealed only 2 clusters suggesting within-school transmission and 3 inter-school clusters, while the remainder was most likely acquired from sources other than those currently attending the school concerned. HIV prevalence in both girls (aOR=3.6, CI 2.9-4.5; p<0.001) and boys (aOR=2.8, CI 1.2-6.2; p=0.01) was higher in those without a living biological mother. The high burden of HIV infection among students was not associated with intra-school transmission in this rural setting. Lack of a living parent is an important factor defining high risk in this group of adolescents.
AIDS Research and Human Retroviruses 07/2014; · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: While HIV subtype-B infected individuals generally progress to AIDS within 8-10 years, limited data exist for other clades, especially from Africa. We investigated rates of HIV disease progression of clade C-infected South African women.
METHODS: Prospective sero-incidence cohorts in KwaZulu-Natal were assessed for acute HIV infection monthly (n=245) or 3-monthly (n=594) for up to four years. Rapid disease progression was defined as CD4 decline to <350 cells/µl by two years post-infection. Serial clinical and laboratory assessments were compared using survival analysis and logistic regression models.
RESULTS: Sixty-two women were identified at median 42 days post-infection (IQR 34-59), contributing 282 person-years of follow-up. Mean CD4 count dropped by 39.6% at 3 months and 46.7% at 6 months post-infection in women with pre-infection measurements. CD4 decline to <350 cells/µl occurred in 31%, 44%, and 55% at 1, 2, and 3 years post-infection, respectively, and to <500 cells/µl in 69%, 79% and 81% at equivalent time-points. Predictors of rapid progression were CD4 count at 3 months post-infection [hazard ratio (HR) 2.07, 95% confidence interval 1.31-3.28, p=0.002], set-point viral load [HR 3.82 (1.51-9.67), p=0.012] and hepatitis B co-infection [HR 4.54 (1.31-15.69), p=0.017]. Conversely, presence of any of HLAB*1302, B*27, B*57, B*5801 or B*8101 alleles predicted non-rapid progression [HR 0.19 (0.05-0.74), p=0.016].
CONCLUSION: Nearly half of subtype C infected women progressed to CD4<350 cells/µl within two years of infection. Implementing 2013 WHO treatment guidelines (CD4<500) would require most individuals to start antiretroviral therapy within one year of HIV infection.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 07/2014;
[Show abstract][Hide abstract] ABSTRACT: Understanding the impact of HIV diversity on immunological responses to candidate immunogens is critical for HIV vaccine development. We investigated the reactivity and immunodominance patterns of HIV-1 consensus group M Gag and Nef in (i) Cameroon, where individuals infected with the predominant CRF02_AG clade were compared with those infected with diverse non-CRF02_AG clades; and (ii) in a multiclade epidemic, namely Cameroon, compared with a monoclade C epidemic, South Africa. We analyzed 57 HIV-infected individuals from Cameroon and 44 HIV-infected individuals from South Africa for differences in detecting HIV-1 consensus M Gag and Nef T cell responses using the IFN-γ ELISpot assay. We found no difference in the predicted epitope coverage between CRF02_AG and non-CRF02_AG viruses for either Gag or Nef. There were no differences in the magnitude and breadth of responses for CRF02_AG and non-CRF02_AG-infected individuals. In contrast, the specificity of epitope targeting was markedly different between the two groups, with fewer than one third (11/28) of peptides commonly recognized. Furthermore, only one peptide was commonly recognized by at least three individuals from both AG and non-AG groups, indicating poor immunodominance. For Nef, more than half of all targeted peptides (14/27) were recognized by both groups, and four peptides were commonly targeted by at least three individuals. Three times more peptides were exclusively targeted in the diverse non-CRF02_AG group compared to the CRF02_AG group (10 vs. 3). Of note, similar results were obtained when South Africa, a monoclade C epidemic, and Cameroon, a multiclade epidemic, were compared. The central nature of HIV-1 consensus M sequences resulted in their broad recognition, but failed to identify highly immunodominant peptides between homogeneous and diverse HIV epidemics.
[Show abstract][Hide abstract] ABSTRACT: Early studies in Cape Town identified independent HIV-1 epidemics, with distinct viral subtypes, among men who have sex with men (MSM) and the heterosexual population. However, few recent HIV-1 subtype data are available for MSM in South Africa. We examined HIV-1 subtypes among MSM in Cape Town.
Self-identified MSM were recruited from geographically and racially disparate communities across Cape Town. Participants completed behavioral questionnaires and underwent HIV testing. Virus isolated from infected participants underwent complete env gp160 sequencing, and HIV-1 subtypes were assigned through phylogenetic analysis.
In total, 194 HIV-infected MSM were enrolled: 67% black African, 24% colored, and 9% white men. More black African men identified as bisexual or heterosexual compared with other races. Overall, 31%-66% of men reported a recent partner of another race. HIV-1 subtypes were confirmed for 143 participants: 81% were subtype C, 14% B, 1% A1, 1% F2, and 3 recombinant viruses. Subtype C virus was associated with black African race (P = 0.003 compared with colored; P < 0.001 compared with white), men who identified as bisexual/heterosexual (P = 0.01), and reported a female sexual partner in the last year (P = 0.02). Compared with previous studies, an increasing prevalence of subtype C virus was noted among white MSM.
This molecular epidemiology study provides novel evidence of sexual network links between the heterosexual and MSM epidemics and between historically racially disparate communities. These findings provide insights into the drivers of HIV epidemics in different population groups and may have implications for prevention strategies.
[Show abstract][Hide abstract] ABSTRACT: Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development.
[Show abstract][Hide abstract] ABSTRACT: Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n=120) or chronic (n=207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r=0.19, p=0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p=0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r=−0.21, p=0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course.
[Show abstract][Hide abstract] ABSTRACT: HIV-1 superinfection occurs when an infected individual acquires a distinct new viral strain. The rate of superinfection may be reflective of the underlying HIV risk in the population. The CAPRISA 004 clinical trial demonstrated that women who used a tenofovir containing microbicide gel had lower rates of HIV infection than women using a placebo gel. Women who contracted HIV-1 during the trial were screened for the occurrence of superinfection by next-generation sequencing of the viral gag and env genes. There were two cases (one in each trial arm) of subtype C superinfection identified from the 76 women with primary infection screened at two timepoints (rate of superinfection=1.5/100 person-years). Both women experienced a greater than 0.5 log increase in viral load during the window when superinfection occurred. The rate of superinfection was significantly lower than the overall primary HIV incidence in the microbicide trial (IRR=0.20; p=0.003). The women who seroconverted during the trial reported a significant increase in sexual contact with their stable partner four months after seroconversion (p<0.001), which may have lowered the risk of superinfection in this population. The lower frequency of SI compared to primary incidence is in contrast to a report from a general heterosexual African population, but agrees with a study of high-risk women in Kenya. A better understanding of the rate of HIV superinfection could have important implications for ongoing HIV vaccine research.
Journal of clinical microbiology 12/2013; · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Identification of the epitopes targeted by antibodies that can neutralize diverse HIV-1 strains can provide important clues for the design of a preventative vaccine.
We have developed a computational approach that can identify key amino acids within the HIV-1 envelope glycoprotein that influence sensitivity to broadly cross-neutralizing antibodies. Given a sequence alignment and neutralization titers for a panel of viruses, the method works by fitting a phylogenetic model that allows the amino acid frequencies at each site to depend on neutralization sensitivities. Sites at which viral evolution influences neutralization sensitivity were identified using Bayes factors (BFs) to compare the fit of this model to that of a null model in which sequences evolved independently of antibody sensitivity. Conformational epitopes were identified with a Metropolis algorithm that searched for a cluster of sites with large Bayes factors on the tertiary structure of the viral envelope.
We applied our method to ID50 neutralization data generated from seven HIV-1 subtype C serum samples with neutralization breadth that had been tested against a multi-clade panel of 225 pseudoviruses for which envelope sequences were also available. For each sample, between two and four sites were identified that were strongly associated with neutralization sensitivity (2ln(BF) > 6), a subset of which were experimentally confirmed using site-directed mutagenesis.
Our results provide strong support for the use of evolutionary models applied to cross-sectional viral neutralization data to identify the epitopes of serum antibodies that confer neutralization breadth.