Variable regions 1 and 2 (V1/V2) of human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein are critical for viral evasion of antibody neutralization, and are themselves protected by extraordinary sequence diversity and N-linked glycosylation. Human antibodies such as PG9 nonetheless engage V1/V2 and neutralize 80% of HIV-1 isolates. Here we report the structure of V1/V2 in complex with PG9. V1/V2 forms a four-stranded β-sheet domain, in which sequence diversity and glycosylation are largely segregated to strand-connecting loops. PG9 recognition involves electrostatic, sequence-independent and glycan interactions: the latter account for over half the interactive surface but are of sufficiently weak affinity to avoid autoreactivity. The structures of V1/V2-directed antibodies CH04 and PGT145 indicate that they share a common mode of glycan penetration by extended anionic loops. In addition to structurally defining V1/V2, the results thus identify a paradigm of antibody recognition for highly glycosylated antigens, which—with PG9—involves a site of vulnerability comprising just two glycans and a strand.

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1–infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.

V2/V3 conformational epitope antibodies that broadly neutralize HIV-1 (PG9 and PG16) have been recently described. Since an elicitation of previously known broadly neutralizing antibodies has proven elusive, the induction of antibodies with such specificity is an important goal for HIV-1 vaccine development. A critical question is which immunogens and vaccine formulations might be used to trigger and drive the development of memory B cell precursors with V2/V3 conformational epitope specificity. In this paper we identified a clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer and inferred their common reverted unmutated ancestor (RUA) antibodies. While conformational epitope antibodies rarely bind recombinant Env monomers, a screen of 32 recombinant envelopes for binding to the CH01 to CH04 antibodies showed monoclonal antibody (MAb) binding to the E.A244 gp120 Env and to chronic Env AE.CM243; MAbs CH01 and CH02 also bound to transmitted/founder Env B.9021. CH01 to CH04 neutralized 38% to 49% of a panel of 91 HIV-1 tier 2 pseudoviruses, while the RUAs neutralized only 16% of HIV-1 isolates. Although the reverted unmutated ancestors showed restricted neutralizing activity, they retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. Thus, E.A244, B.9021, and AE.CM243 Envs are three potential immunogen candidates for studies aimed at defining strategies to induce V2/V3 conformational epitope-specific antibodies.

This study aimed to describe the prevalence and predictors for male partner participation in HIV voluntary counselling and testing (VCT) at two primary healthcare clinics in Moshi urban, Tanzania as well as the effect of partner participation on uptake of HIV perinatal interventions. Pregnant women (n = 2654) in their third trimester, participating in a prevention of mother to child tranmission (PMTCT) program between June 2002 and March 2004 were encouraged to inform and invite their partners for HIV-VCT. Trained nurses conducted pre-test counselling, interviews, clinical examinations and blood sampling from the participating women and their partners. Test results were presented and post-test counselling was conducted individually or in couples, depending on the wishes of the participants. Three-hundred-and-thirty-two male partners (12.5%) came for HIV-VCT. A high proportion (131; 40%) came after the woman had delivered. HIV-seropositive women whose partners attended were three times more likely to use Nevirapine prophylaxis, four times more likely to avoid breastfeeding and six times more likely to adhere to the infant feeding method selected than those whose partners didn't attend. Women were more likely to bring their partner for VCT if they collected their own test results, were living with their partner, had a high monthly income and had expressed at enrolment the intention to share HIV results with their partner. Although PMTCT programs are presumably a good entry point for male involvement in prevention of sexual and perinatal HIV transmission, this traditional clinic-based approach reaches few men. Given the positive influence male participation has on the acceptance of perinatal interventions, a different approach for promoting male participation in VCT is urgently required. Within PMTCT programs, counseling should emphasize the advantages of partner participation to encourage women to inform and convince male partners to come for VCT. Also, promotion of couple VCT outside antenatal settings in male friendly and accessible settings should be given priority.