Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design.

SUMMARY Introduction Heterosexual HIV-1 transmission is an inefficient process with rates reported at <1% per unprotected sexual exposure. When transmission occurs, systemic infection is typically established by a single genetic variant, taken from the swarm of genetically distinct viruses circulating in the donor. Whether that founder virus represents a chance event or was systematically favored is unclear. Our work has tested a central hypothesis that founder virus selection is biased toward certain genetic characteristics. Rationale If HIV-1 transmission involves selection for viruses with certain favorable characteristics, then such advantages should emerge as statistical biases when viewed across many viral loci in many transmitting partners. We therefore identified 137 Zambian heterosexual transmission pairs, for whom plasma samples were available for both the donor and recipient partner soon after transmission, and compared the viral sequences obtained from each partner to identify features that predicted whether the majority amino acid observed at any particular position in the donor was transmitted. We focused attention on two features: viral genetic characteristics that correlate with viral fitness, and clinical factors that influence transmission. Statistical modeling indicates that the former will be favored for transmission, while the latter will nullify this relative advantage. Results We observed a highly significant selection bias that favors the transmission of amino acids associated with increased fitness. These features included the frequency of the amino acid in the study cohort, the relative advantage of the amino acid with respect to the stability of the protein, and features related to immune escape and compensation. This selection bias was reduced in couples with high risk of transmission. In particular, significantly less selection bias was observed in women and in men with genital inflammation, compared to healthy men, suggesting a more permissive environment in the female than male genital tract. Consistent with this observation, viruses transmitted to women were characterized by lower predicted fitness than those in men. The presence of amino acids favored during transmission predicted which individual virus within a donor was transmitted to their partner, while chronically infected individuals with viral populations characterized by a predominance of these amino acids were more likely to transmit to their partners. Conclusion These data highlight the clear selection biases that benefit fitter viruses during transmission in the context of a stochastic process. That such biases exist, and are tempered by certain risk factors, suggests that transmission is frequently characterized by many abortive transmission events in which some target cells are nonproductively infected. Moreover, for efficient transmission, some changes that favored survival in the transmitting partner are frequently discarded, resulting in overall slower evolution of HIV-1 in the population. Paradoxically, by...

In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I) -associated amino acid polymorphisms, presumed to refl ect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a signifi cant correlation between the number of Gag escape mutations targeted by specifi c HLA-B allele -restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specifi c CTL responses capable of driving virus escape in the donor may be of clinical benefi t to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fi tness costs could have a signifi cant impact on HIV-1 pathogenesis.

HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade–infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703–restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703–restricted CTL responses. In HLA-B*5703–mismatched recipients, the previously described early benefit of transmitted HLA-B*5703–associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.

Host genetic factors have been reported to influence the natural history of hepatitis C virus (HCV) infection. We examined whether variation in interleukin 10 (IL-10) and tumor necrosis factor ␣ (TNF-␣) genes would predict the likelihood of sustained response to antiviral therapy. Single nucleotide polymorphisms (SNPs) and microsatellites at two loci encoding the cytokines IL-10 and TNF-␣ were determined by polymerase chain reaction (PCR)-based techniques. Their relationship to the outcome of antiviral therapy for chronic HCV infection was studied in 49 white patients who had a virologically sustained response (SR) and in 55 white nonresponders (NR) to a combination of interferon alfa-2b and ribavirin (IFN ؉ R). Several IL-10 variants were more frequent among SRs compared with NRs. Carriage of the ؊592A or the ؊819T SNP was associated with SR (odds ratio [OR] ‫؍‬ 2.2; P ‫؍‬ .016). The ؊592A/A and the exclusively linked ؊819T/T genotypes were also associated with SR (OR ‫؍‬ 16.6; P ‫؍‬ .013 for either). The haplotype consisting of the 108-bp IL-10.R microsatellite and ؊3575T, ؊2763C, ؊1082A, ؊819T, ؊592A was also associated with SR (OR ‫؍‬ 2.65; P ‫؍‬ .01). Stratification for viral genotype, baseline viral RNA concentration, and histologic status identified homozygosity for the haplotype as the principal determinant: all 5 homozygous individuals achieved SR (OR crude ‫؍‬ 13.7; P ‫؍‬ .025; stratified ORs ‫؍‬ 1.9-7.0), whereas heterozygotes differed only slightly from wild-type carriers. In contrast, TNF alleles defined by promoter sequences ؊238G/A and ؊308G/A were approximately equally distributed among SR and NR. In conclusion, homozygosity for ؊592A, ؊819T or the extended haplotype (108bp) ؊ ( During the last decade, treatment for hepatitis C virus (HCV) infection has rapidly improved. Interferon alfa-2b in combination with ribavirin (IFN ϩ R) has become the standard regimen for HCV infection. Sustained response (SR) to IFN ϩ R, defined as undetectable HCV RNA at 6 months after discontinuation of therapy, is achievable in 30% to 60% of treated patients.