on behalf of the CAPRISA 004 Trial Group ‡ The Centre for the AIDS Program of Research in South Africa (CAPRISA) 004 trial assessed the effectiveness and safety of a 1% vaginal gel formulation of tenofovir, a nucleotide reverse transcriptase inhibitor, for the prevention of HIV acquisition in women. A double-blind, randomized controlled trial was conducted comparing tenofovir gel (n = 445 women) with placebo gel (n = 444 women) in sexually active, HIV-uninfected 18-to 40-year-old women in urban and rural KwaZulu-Natal, South Africa. HIV serostatus, safety, sexual behavior, and gel and condom use were assessed at monthly follow-up visits for 30 months. HIV incidence in the tenofovir gel arm was 5.6 per 100 women-years (person time of study observation) (38 out of 680.6 women-years) compared with 9.1 per 100 women-years (60 out of 660.7 women-years) in the placebo gel arm (incidence rate ratio = 0.61; P = 0.017). In high adherers (gel adherence > 80%), HIV incidence was 54% lower (P = 0.025) in the tenofovir gel arm. In intermediate adherers (gel adherence 50 to 80%) and low adherers (gel adherence < 50%), the HIV incidence reduction was 38 and 28%, respectively. Tenofovir gel reduced HIV acquisition by an estimated 39% overall, and by 54% in women with high gel adherence. No increase in the overall adverse event rates was observed. There were no changes in viral load and no tenofovir resistance in HIV seroconverters. Tenofovir gel could potentially fill an important HIV prevention gap, especially for women unable to successfully negotiate mutual monogamy or condom use. W omen are disproportionately affected by the Acquired Immunodeficiency Syndrome (AIDS) epidemic in Africa, the region that accounts for 70% of global burden of Human Immunodeficiency Virus (HIV) infection (1). Current HIV prevention behavioral messages on abstinence, faithfulness, and condom promotion have had limited impact on HIV incidence rates in women, especially in sub-Saharan Africa, where young women bear the greatest HIV burden (2). The search for new technologies to prevent sexually transmitted HIV infection over the past three decades has had limited success. Only five of 37 randomized controlled trials, which tested 39 HIV prevention strategies, have demonstrated protection against sexual transmission of HIV infection (3). The successful trials tested medical male circumcision in South Africa (4), Kenya (5), and Uganda (6) (combined effectiveness in reducing HIV acquisition was 57%), sexually transmitted infection (STI) treatment in Tanzania (effectiveness in reducing HIV acquisition was 42%) (7), and a HIV vaccine combination in Thailand (effectiveness in reducing HIV acquisition was 31%) (8). Hence, HIV prevention technologies that women can use and control remain a pressing priority (9).Microbicides are products that can be applied to the vagina or rectum with the intention of reducing the acquisition of STIs, including HIV. An effective microbicide has the potential to alter the trajectory of the global HIV pandemic (10). Over the ...

Summary 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 CAPRISA-donor CAP256; each antibody contained the protruding tyrosine-sulfated, anionic antigen-binding loop (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 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, an important vaccine insight.

SARS-CoV-2 501Y.V2 (B.1.351), a novel lineage of coronavirus causing COVID-19, contains substitutions in two immunodominant domains of the spike protein. Here, we show that pseudovirus expressing 501Y.V2 spike protein completely escapes three classes of therapeutically relevant antibodies. This pseudovirus also exhibits substantial to complete escape from neutralization, but not binding, by convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and foreshadows reduced efficacy of spike-based vaccines. Individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), develop neutralizing antibodies that can persist for months 1,2. Neutralizing antibodies are considered the primary correlate of protection from infection and are being pursued as therapeutics 3,4. Interim analyses with monoclonal neutralizing antibodies have shown success, facilitating their authorization for emergency use 5,6. The SARS-CoV-2 receptor binding domain (RBD) exists in either an 'up' (receptor-accessible) or 'down' (receptor-shielded) conformation. RBD is the dominant neutralization target for this and other human coronaviruses 7,8. These antibodies can be broadly divided into four main classes, of which two overlap with the angiotensin converting enzyme 2 (ACE2) receptor binding site (Fig. 1a and Supplementary Fig. 1a) 9. Class 1 antibodies are most frequently elicited in SARS-CoV-2 infection and include a public antibody response to an epitope only accessible in the RBD 'up' conformation 10. Class 2 antibodies use more diverse VH-genes and bind to RBD 'up' and RBD 'down' conformations of spike. After RBD, the N-terminal domain (NTD) of spike is the next most frequently targeted by neutralizing antibodies, most of which target a single immunodominant site 11. We, and others, recently described a new SARS-CoV-2 lineage in South Africa, defined as Nextstrain clade 20H/501Y.V2 (PANGOLin lineage B.1.351) 12. This lineage is defined by nine

The HIV-1-envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a postfusion state. As the sole viral antigen on the HIV-1-virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5-Å resolution for an HIV-1-Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the prefusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Prefusion gp41 encircles N- and C-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry likely involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the prefusion closed spike: we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.