HIV vaccine, Tx advances highlighted

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New and emerging biomedical pre-exposure prophylaxis (PrEP) approaches to prevent HIV infection in targeted high-risk populations offer the most effective near-term strategy to reduce HIV transmission. The latest outcomes research, clinical trials results, and advances in HIV vaccine development are highlighted in multiple articles that comprise the annual HIV Prevention Science issue of AIDS Research and Human Retroviruses.

In the article Exploring Antibody Potential as Prophylactic/Therapeutic Strategies for Prevention of Early Mucosal HIV-1 Infection, Bin Su and co-authors from Université de Strasbourg, Hôpital de Hautepierre (Strasbourg, France), and Hôpital Henri Mondor (Créteil, France) demonstrate the ability of broadly neutralising antibodies to prevent HIV infection of CD4+ T lymphocytes by inhibiting cell-to-cell HIV transmission. The antibody mixture also had a role in decreasing HIV replication. The researchers used a co-culture system to model the types of cells and conditions present in the genital mucosal tissues where sexual transmission of HIV occurs.

Rebecca Pellett Madan and colleagues from Albert Einstein College of Medicine (Bronx, NY), University of Cape Town (South Africa), Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, National Health Laboratory Service (Durban, South Africa), and Massachusetts Institute of Technology (Cambridge, MA) examine the relationship between antibacterial activity in a woman’s genital tract and her risk for acquiring HIV. The researchers show that women with higher inhibitory activity against E. coli bacteria and higher levels of antimicrobial peptides in cervicovaginal samples had an increased risk of HIV infection. They report their findings in the article Innate Antibacterial Activity in Female Genital Tract Secretions is Associated with Increased Risk of HIV Acquisition .

In the perspective article A Shot in the Arm for HIV Prevention? Recent Successes & Critical Threshold, Dr Thomas Hope, editor-in-chief of AIDS Research and Human Retroviruses and professor of cell and molecular biology at Northwestern University, Feinberg School of Medicine and Dr Jeanne Marrazzo, professor of medicine, University of Washington (Seattle), state: “Efforts to decrease the spread of HIV worldwide continue at a rapid pace. With the development of new biomedical interventions and findings from pivotal clinical trials, a new framework for short and long-term prevention strategies is emerging.”

Abstract 1
Mucosal tissues are the predominant sites for genital HIV-1 transmission. We investigated the mechanisms by which broadly neutralizing antibodies (bNAbs) inhibit HIV-1 replication in a coculture model including primary mucosal dendritic cells (DCs), such as Langerhans cells, interstitial dendritic cells, and CD4+ T lymphocytes. We show that bNAbs efficiently prevent HIV-1 infection by inhibiting HIV-1 transmission to CD4+ T lymphocytes. This inhibition of cell-to-cell transmission was observed with equal potency as the inhibition of cell-free infection of primary CD4+ T lymphocytes. In addition, a decrease in HIV-1 replication in DCs and the induction of DC maturation were detected. This additional inhibition was Fc mediated as it was blocked by the use of specific anti-FcγR monoclonal Abs. The DC maturation by bNAbs during HIV transmission may contribute to mucosal protection. Therefore, multiple antibody-mediated inhibitory functions should be combined for the improvement of future preventive/therapeutic strategies to cure HIV.

Abstract 2
Greater inhibitory activity against Escherichia coli and levels of human β defensin (HBD)-2 in genital tract secretions predicted HIV acquisition in women in the HPTN 035 trial. We investigated whether higher levels of E. coli inhibitory activity and antimicrobial peptides in cervicovaginal lavage (CVL) samples predicted HIV acquisition in women in the CAPRISA 002 Acute Infection Study. E. coli inhibitory activity and antimicrobial peptides were quantified in CVL from a subset of CAPRISA 002 participants who did not seroconvert (n=39) and from seroconverting women prior to infection (n=17) and during acute infection (n=11). Women who acquired HIV had significantly greater preinfection CVL E. coli inhibitory activity (p=0.01) and HBD-1 levels (p=0.02) compared to women who remained uninfected. Preinfection E. coli inhibitory activity remained significantly associated with seroconversion following adjustment for the presence of bacterial vaginosis (OR 1.45; 95% CI 1.07, 1.97). Partial least squares discriminant analysis confirmed that preinfection CVL E. coli inhibitory activity, together with higher CVL concentrations of HBD-1 and secretory leukocyte protease inhibitor, distinguished seroconverters from nonseroconverters with 67% calibration accuracy. CVL concentrations of human neutrophil peptides (HNP) 1–3 increased significantly with acute infection (p=0.001) and correlated with plasma viral set point (r=0.66, p=0.03). E. coli inhibitory activity in genital tract secretions could provide a biomarker of HIV risk. The correlation between HNP 1–3 and viral set point merits further investigation of the relationship between mucosal inflammation during early HIV infection and disease progression.

Abstract 3
Efforts to decrease the spread of HIV worldwide continue at a rapid pace. With the development of new biomedical interventions and findings from pivotal clinical trials, a new framework for short-term and long-term prevention strategies is emerging. It is clear that biomedical-based approaches targeted at the highest risk populations have the greatest potential to have a short-term impact. Unfortunately, challenges with adherence in healthy populations at risk are now well-recognized, and competing health care priorities in the context of fragile delivery infrastructures pose formidable obstacles to implementation. We need better ways to identify high-risk populations, sophisticated understanding of the behavioral parameters that can ensure adherence, and the development of better strategies to provide sustained delivery of preexposure prophylaxis (PrEP). In the long term, we need an effective vaccine—a path that has proven to be rocky. Research facilitating an increased understanding of immune responses and what represents effective responses to prevent HIV acquisition should facilitate progress. While we wait for that time, PrEP offers the best strategy for short-term impact.

Liebert Publications material
AIDS Research and Human Retroviruses special issue
AIDS Research and Human Retroviruses abstract 1
AIDS Research and Human Retroviruses abstract 2
AIDS Research and Human Retroviruses perspective article

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