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During sexual transmission of HIV in women, the first cells likely to be infected are submucosal CD4+ T cells and dendritic cells of the lower genital tract. HIV is segregated from these target cells by an epithelial cell layer that can be bypassed even when healthy and intact. To understand how HIV penetrates this barrier, we identified a host protein, gp340, that is expressed on genital epithelium and binds the HIV envelope via a specific protein-protein interaction. This binding allows otherwise subinfectious amounts of HIV to efficiently infect target cells and allows this infection to occur over a longer period of time after binding. Our findings suggest a mechanism of viral entry during heterosexual transmission where HIV is bound to intact genital epithelia, which then promotes the initial events of infection. Understanding this step in the initiation of infection will allow for the development of tools and methods for blocking HIV transmission.

The T-20 peptide targets the HIV envelope glycoprotein, inducing dose-dependent reductions in plasma HIV RNA that are equivalent to those induced by existing drugs ( ).

Epitopes located in and around the coreceptor binding site of gp120 represent some of the most conserved and functionally important sequences in the HIV envelope. Many of these epitopes can be exposed prior to and/or after attachment in a manner determined by envelope sequence and infection system. Furthermore, these epitopes are immunogenic in humans and elicit cognate antibodies exhibiting a range of structures and fine specificities. These features suggest that CD4i epitopes should be carefully evaluated for potential utility in vaccine development. Experiments to evaluate the relevance of anti-CD4i responses to the course and fate of HIV infection will be discussed.

Almost 10 years ago, Ryser et al[1][1] reported that cleavage of 2 disulfide bonds in the gp120 surface component of the HIV-1 envelope is required for virion entry into CD4-bearing cells and that cell surface protein disulfide isomerase (PDI) is responsible for this effect. Since that initial

The Food and Drug Administration in the United States has approved final phase clinical trials for the world's first AIDS vaccine. The vaccine, known as AIDSVAX, is based on gp120, an HIV envelope glycoprotein that interacts with and binds to T cell surface receptors. It is manufactured by VaxGen, a subsidiary of Genentech. The vaccine will be tested on 5000 US volunteers who have tested negative for HIV but are at high risk of contracting AIDS through sexual contact, and on 2500 volunteers from Thailand who are injecting drug users. These …

HIV SHARED center stage at the XI International Conference on AIDS with another potent infectious agent: optimism. Throughout the 5-day meeting, researchers pointed to the use of combination antiretroviral therapy and viral load measurements to monitor disease progression as the gateway to a new era in managing HIV disease as a chronic illness. "We've actually turned a page and opened a new chapter in the history of the pandemic," said Martin T. Schechter, MD, PhD, cochair of the conference in Vancouver, British Columbia, and national director of the Canadian HIV Trials Network. "Many things that we once thought were impossible are now at least within the realm of the achievable." Such enthusiasm is warranted, but it should be tempered with caution, noted Scott Hammer, MD, director of the Research Virology Laboratory at Deaconess Hospital in Boston, Mass. "The degree of meaningful clinical benefit with the newer regimens and strategies needs

The role of the glycans of the mature human immunodeficiency virus (HIV) envelope (gp160) in its stability in various conditions was studied. gp160 conformation was monitored through its subsequent ability to bind [125I]CD4. Treatment of glycosylated (CHO+) gp160 with (i) sodium dodecyl sulfate (SDS) concentrations above 0.01% impaired subsequent CD4 binding while 0.3% SDS abolished it; (ii) beta-mercaptoethanol (MSH) concentrations above 0.01% impaired CD4 binding while 0.03% MSH abolished it; (iii) 2 M guanidine-HCl had no effect; (iv) temperatures between 50 degrees C and 80 degrees C altered CD4 binding while, above 80 degrees C, the binding was abolished; (v) CD4 binding was decreased by 50% by 2 freeze-thaw cycles but was not further affected by subsequent (up to 15) cycles; (vi) gp160 incubation in serum or cell lysate had no effect on CD4 binding. Glycanase treated (CHO-) gp160 binding activity was only 3-fold lower than that of CHO+ gp160. Only 2 M guanidine-HCl and heating at 70 degrees C differentially affected the binding of CHO+ and CHO- gp160, the effects being larger for CHO- gp160. CHO- gp160 binding was impaired after incubation in either serum or cell lysate. Thus, glycans stabilize gp160 conformation in some environments. However, CHO- gp160 appears to be resistant to denaturation as compared to other glycoproteins reported in the literature.

Passive transfer of antibodies has long been considered a potential treatment modality for infectious diseases, including HIV. Early efforts to use antibodies to suppress HIV replication, however, were largely unsuccessful, as the antibodies that were studied neutralized only a relatively narrow spectrum of viral strains and were not very potent. Recent advances have led to the discovery of a large portfolio of human monoclonal antibodies that are broadly neutralizing across many HIV-1 subtypes and are also substantially more potent. These antibodies target multiple different epitopes on the HIV envelope, thus allowing for the development of antibody combinations. In this review, we discuss the application of broadly neutralizing antibodies (bNAbs) for HIV treatment and HIV eradication strategies. We highlight bNAbs that target key epitopes, such as the CD4 binding site and the V2/V3-glycan-dependent sites, and we discuss several bNAbs that are currently in the clinical development pipeline.

Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine.

We have studied the biologic and physical properties of a monoclonal antibody that binds to gp120, the exterior envelope glycoprotein of the human immunodeficiency virus (HIV) strain HTLV-IIIB. Designated 9284, the antibody possesses viral neutralizing activity and inhibits syncytium formation by infected cells. The antibody recognized a region of the polypeptide backbone previously described as an important neutralizing epitope. This region lies 307-330 residues from amino terminus of the glycoprotein. We have compared the biologic and physical properties of this antibody to those of the recently described 0.5 beta monoclonal antibody to gp120. The 0.5 beta antibody was biologically more potent and bound an epitope slightly downstream to that of the 9284 antibody. The antibodies did not differ significantly in their affinity for gp120. In competition studies, the 0.5 beta antibody was displaced by the 9284 antibody, but the binding of the latter was unaffected by 0.5 beta.

One of the many bottlenecks standing before a rational approach to vaccine design against HIV is the lack of epidemiological evidence that immune responses to the virus are able to influence the course of infection or the disease process.

BackgroundHarnessing CD4+ T cell help in the lymph nodes through rational antigen design could enhance formation of broadly neutralizing antibodies (bNAbs) during experimental HIV immunization. This process has remained hidden due to difficulty with direct study, with clinical studies instead focusing on responses in the blood as a proxy for the secondary lymphoid tissue.MethodsTo address this, lymph node cells (LNC) were collected using ultrasound guided fine needle aspiration of axillary lymph nodes from 11 HIV negative participants in an experimental HIV immunogen study (European AIDS Vaccine Initiative EAVI2020_01 study, NCT04046978). Cells from lymph node and blood (PBMC), were collected after intramuscular injection with HIV Env Mosaic immunogens based on HIV Envelope glycoprotein and combined with a liposomal toll-like receptor-4 adjuvant; monophosphoryl lipid A. Simultaneously sampled cells from both blood and lymph node in the same donors were compared for phenotype, function, and antigen-specificity.ResultsUnsupervised cluster analysis revealed tissue-specific differences in abundance, distribution, and functional response of LNC compared with PBMC. Monocytes were virtually absent from LNC, which were significantly enriched for CD4+ T cells compared with CD8+ T cells. T follicular helper cells with germinal center features were enriched in LNC, which contained specific CD4+ and CD8+ T cell subsets including CD4+ T cells that responded after a single injection with HIV Env Mosaic immunogens combined with adjuvant. Tissue-specific differences in response to an MHC-II dependent superantigen, staphylococcal enterotoxin B, indicated divergence in antigen presentation function between blood and lymph node.ConclusionsLNC are phenotypically and functionally distinct from PBMC, suggesting that whole blood is only a limited proxy of the T cell lymphatic response to immunization. HIV-specific CD4+ T cells in the lymph node are rapidly inducible upon experimental injection with HIV immunogens. Monitoring evolution of CD4+ T cell memory in LNC with repeated experimental HIV immunization could indicate the strategies most likely to be successful in inducing HIV-specific bNAbs.