A high level of V1V2-specific IgG antibodies in vaccinees' sera was the only independent variable that correlated with a reduced risk of HIV acquisition in the RV144 clinical trial. In contrast, IgG avidity, antibody neutralization, and antibody-dependent cellular cytotoxicity each failed as independent correlates of infection. Extended analyses of RV144 samples demonstrated antiviral activity of V1V2-specific vaccine-induced antibodies. V2-specific antibodies have also been associated with protection from SIV, and the V2i-specific subset of human monoclonal antibodies (mAbs), while poor neutralizers, mediate Fc-dependent antiviral functions The objective of this study was to determine the protective efficacy of a V2i-specific human mAb 830A against mucosal SHIV challenge. V2i mAb binding sites overlap the integrin binding site in the V2 region and are similar to the epitopes bound by antibodies associated with reduced HIV infection rate in RV144. Because the IgG3 subclass was a correlate of reduced infection rate in RV144, we compared passive protection by both IgG1 and IgG3 subclasses of V2i mAb 830A. This experiment represents the first test of the hypothesis emanating from RV144 and SIV studies that V2i Abs can reduce infection risk. The results show that passive transfer with a single V2i mAb, IgG1 830A, reduced plasma and PBMC virus levels and decreased viral DNA in lymphoid tissues compared to controls, but too few animals remained uninfected to achieve significance in reducing infection risk. Based on these findings, we conclude that V2i antibodies can impede viral seeding following mucosal challenge, resulting in improved viral control. Since the results of the HIV RV144 clinical trial were reported, there has been significant interest in understanding how protection was mediated. Antibodies directed to a subregion of the Envelope protein called V1V2 were directly correlated with reduced risk, and surprisingly low virus neutralization was observed. To determine whether these antibodies alone could mediate protection, we used a human monoclonal antibody directed to V2 with properties similar to those elicited in the vaccine trial for passive infusions in rhesus macaques and challenge with SHIV. The single V2 antibody at the dose given did not significantly reduce the number of infections, but there was a significant reduction in seeding of virus to the lymph nodes and a decrease in plasma viremia in the HIV antibody-infused macaques compared with the control antibody-infused animals. This finding shows that V2 antibodies mediate antiviral activities that could contribute to a protective HIV vaccine.

Vertical transmission accounts for most human immunodeficiency virus (HIV) infection in children, and treatments for newborns are needed to abrogate infection or limit disease progression. We showed previously that short-term broadly neutralizing antibody (bNAb) therapy given 24 h after oral exposure cleared simian-human immunodeficiency virus (SHIV) in a macaque model of perinatal infection. Here, we report that all infants given either a single dose of bNAbs at 30 h, or a 21-day triple-drug ART regimen at 48 h, are aviremic with almost no virus in tissues. In contrast, bNAb treatment beginning at 48 h leads to tight control without adaptive immune responses in half of animals. We conclude that both bNAbs and ART mediate effective post-exposure prophylaxis in infant macaques within 30-48 h of oral SHIV exposure. Our findings suggest that optimizing the treatment regimen may extend the window of opportunity for preventing perinatal HIV infection when treatment is delayed.

Highlights d Macaque immunogenicity studies with glycosylated V1V2 multimeric scaffold proteins d V1V2-scaffold immunogens induce V1V2-specific plasma and mucosal antibodies d V1V2 antibodies are functionally active and durable with increasing affinity d V1V2-scaffold immunogen cocktails made from multiple viruses improve humoral responses

Hoxa9 and Flt3 signaling are individually important for the generation of lymphoid lineage precursors from multipotent hematopoietic progenitors (MPP) in bone marrow (BM). Mice deficient for Hoxa9, Flt3, or Flt3-ligand (FL) have reduced numbers of lymphoid-primed multipotential progenitors (LMPP), common lymphoid progenitors (CLP), and B/T cell precursors. Hoxa9 regulates lymphoid development, in part, through transcriptional regulation of Flt3. However, it was unclear if Hoxa9 has functions in lymphopoiesis independent of, or alternatively, synergistically with Flt3 signaling. Here we show that Hoxa9−/−Flt3l−/− mice have more severe deficiencies in all B lineage cells, CLP, LMPP, and total Flt3+ MPP in BM than the single knockouts. Although LMPP and Flt3+ CLP contain precursors for NK and DC lineage cells, no deficiencies in these lineages beyond that in Flt3l−/− mice was found. Thymocyte cellularity was significantly reduced in the compound knockout although peripheral T cell numbers mirrored Flt3l−/− mice. Analysis of the hematopoietic progenitor compartment revealed elevated numbers of CD150+hi CD34− CD41+ myeloid-biased stem cells in Hoxa9−/−Flt3l−/− mice. In contrast, CD150− MPP enriched for lymphoid potential were synergistically reduced, suggesting Hoxa9 and Flt3 signaling function coordinately to regulate lymphopoiesis at a very early stage. Realtime PCR analysis of CD150− Flt3+ cells from WT control, Hoxa9−/−, and Flt3l−/− single knockouts revealed decreased lymphoid transcripts, corroborating the importance of these regulators in lymphoid development. Together, these studies reveal a very early checkpoint in lymphopoiesis dependent on the combinatorial activities of Hoxa9 function and Flt3 signaling.

Despite substantial progress in confronting the global HIV-1 epidemic since its inception in the 1980s, better approaches for both treatment and prevention will be necessary to end the epidemic and remain a top public health priority. Antiretroviral therapy (ART) has been effective in extending lives, but at a cost of lifelong adherence to treatment. Broadly neutralizing antibodies (bNAbs) are directed to conserved regions of the HIV-1 envelope glycoprotein trimer (Env) and can block infection if present at the time of viral exposure. The therapeutic application of bNAbs holds great promise, and progress is being made toward their development for widespread clinical use. Compared to the current standard of care of small molecule-based ART, bNAbs offer: (1) reduced toxicity; (2) the advantages of extended half-lives that would bypass daily dosing requirements; and (3) the potential to incorporate a wider immune response through Fc signaling. Recent advances in discovery technology can enable system-wide mining of the immunoglobulin repertoire and will continue to accelerate isolation of next generation potent bNAbs. Passive transfer studies in pre-clinical models and clinical trials have demonstrated the utility of bNAbs in blocking or limiting transmission and achieving viral suppression. These studies have helped to define the window of opportunity for optimal intervention to achieve viral clearance, either using bNAbs alone or in combination with ART. None of these advances with bNAbs would be possible without technological advancements and expanding the cohorts of donor participation. Together these elements fueled the remarkable growth in bNAb development. Here, we review the development of bNAbs as therapies for HIV-1, exploring advances in discovery, insights from animal models and early clinical trials, and innovations to optimize their clinical potential through efforts to extend half-life, maximize the contribution of Fc effector functions, preclude escape through multiepitope targeting, and the potential for sustained delivery.