Role of the epithelium in human papillomavirus and human immunodeficiency virus infections in the female genital tract.

Background: Two-thirds of people living with human immunodeficiency virus type 1 (HIV-1) infection reside in Sub-Saharan Africa, where there are the highest prevalence and incidence rates of human papillomavirus (HPV) infection. Both infections are sexually transmitted and enter the body via the epithelium. This review describes the extent of involvement of the epithelium in each infection in the female genital tract.

Recent Advances and New Challenges in Cisgender Women's Gynecologic and Obstetric Health in the Context of HIV.

Although rates of human immunodeficiency virus (HIV) have declined globally over the past 10 years, United Nations Programme on HIV/AIDS estimates 1.7 million new infections occurred in 2019, with cisgender women (cis women) and girls accounting for 48%. Acquired immune deficiency syndrome-related illnesses are the leading global cause of mortality in cis women aged 15 to 49, and in many sub-Saharan Africa countries, young women face substantially higher HIV risk than their male counterparts.

Localized cyclical variations in immunoproteins in the female genital tract and the implications on the design and assessment of mucosal infection and therapies.

Problem: Fluctuating hormones regulate reproductive processes in the female genital tract. Consequent changes in the local immunological environment are likely to affect cellular interaction with infectious agents and the assessment of therapies that target mucosal infections.

Method Of Study: We compared Softcup and Weck-Cel sampling protocols and assessed the changes in the concentrations of 39 soluble proteins with menstrual cycle progression in the mucosal and peripheral compartments.

Lower concentrations of chemotactic cytokines and soluble innate factors in the lower female genital tract associated with the use of injectable hormonal contraceptive.

Progesterone-based injectable hormonal contraceptives (HCs) potentially modulate genital barrier integrity and regulate the innate immune environment in the female genital tract, thereby enhancing the risk of STIs or HIV infection. We investigated the effects of injectable HC use on concentrations of inflammatory cytokines and other soluble factors associated with genital epithelial repair and integrity. The concentrations of 42 inflammatory, regulatory, adaptive growth factors and hematopoietic cytokines, five matrix metalloproteinases (MMPs), and four tissue inhibitors of metalloproteinases (TIMPs) were measured in cervicovaginal lavages (CVLs) from 64 HIV-negative women using injectable HCs and 64 control women not using any HCs, in a matched case-control study.

How can we design better vaccines to prevent HIV infection in women?

The human immunodeficiency virus (HIV) burden in women continues to increase, and heterosexual contact is now the most common route of infection worldwide. Effective protection of women against HIV-1 infection may require a vaccine specifically targeting mucosal immune responses in the female genital tract (FGT). To achieve this goal, a much better understanding of the immunology of the FGT is needed.

HIV disease progression in seroconvertors from the CAPRISA 004 tenofovir gel pre-exposure prophylaxis trial.

Background: Although antiretroviral pre-exposure prophylaxis prevents HIV acquisition, it is not known if it alters HIV disease progression. This study assesses whether tenofovir gel impacted on disease progression among CAPRISA 004 microbicide trial seroconvertors.

Methods: Eighty-three seroconvertors from the tenofovir and placebo gel arms of the CAPRISA 004 trial were monitored prospectively for a minimum of 2 years by CD4 count and viral load (VL).

Women with pregnancies had lower adherence to 1% tenofovir vaginal gel as HIV preexposure prophylaxis in CAPRISA 004, a phase IIB randomized-controlled trial.

Background: Antiretroviral prophylaxis may be a critical strategy to reduce periconception HIV transmission. Maximizing the benefit of periconception pharmacologic HIV risk-reduction requires an understanding of the links between pregnancy and adherence to this prevention strategy.

Methods: We assessed study gel adherence among women with pregnancies compared to women without pregnancies enrolled in the CAPRISA 004 phase IIB trial of 1% vaginal tenofovir gel.

Recommendations for the follow-up of study participants with breakthrough HIV infections during HIV/AIDS biomedical prevention studies.

Objective: To facilitate collection of cumulative data on longitudinal HIV disease outcomes during HIV prevention studies by developing recommendations for follow-up of the relatively few study participants with breakthrough infections.

Design: We formed a working group to compare and contrast the various approaches taken in recent HIV prevention trials, to summarize the advantages and disadvantages associated with each, and to explore the feasibility of developing protocols for the long-term follow-up of seroconverters.

Methods: We reviewed study designs, objectives, and assessments in 15 interventional studies that followed HIV seroconverters.

From the laboratory to clinical trials and back again: lessons learned from HIV prevention trials.

Problem: Inadequate, irrelevant, or inappropriate timing of biological specimen collection during clinical trials is a cause for delay in understanding and explaining correlates of protection and/or effectiveness, particularly at the portal of entry in the context of sexual HIV transmission and its prevention.

Methods: We present examples of HIV prevention trials to illustrate the impact of preplanned versus unplanned laboratory science program on the interpretation of trial results and advancement of the field.

Results: Of the five completed pre-exposure prophylaxis trials, only two announced main outcome results simultaneously with data on correlates of drug-related effectiveness.

Safety of tenofovir gel, a vaginal microbicide, in South African women: results of the CAPRISA 004 Trial.

Background: Tenofovir gel, used vaginally before and after coitus, reduced women's acquisition of HIV by 39%. This is a safety assessment of tenofovir gel, including renal, bone, gastrointestinal, genital and haematological parameters.

Methods: In the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, a double-blind, randomized placebo-controlled trial, 445 of the 889 eligibly enrolled women were assigned to tenofovir gel.

Innate immune activation enhances hiv acquisition in women, diminishing the effectiveness of tenofovir microbicide gel.

The antiretroviral agent, tenofovir, formulated as a vaginal microbicide gel, reduces human immunodeficiency virus (HIV) acquisition by 39% in women. This study assessed the role of preexisting immune activation in HIV acquisition in women from the CAPRISA 004 trial, to identify potential strategies to increase the effectiveness of tenofovir gel. Systemic cytokine and cellular immune mediators (platelets and natural killer [NK] cells) were assessed in women at high risk for HIV assigned to either tenofovir or placebo gel in the CAPRISA 004 trial.

The development of CD4 binding site antibodies during HIV-1 infection.

Broadly neutralizing antibodies to the CD4 binding site (CD4bs) of gp120 are generated by some HIV-1-infected individuals, but little is known about the prevalence and evolution of this antibody response during the course of HIV-1 infection. We analyzed the sera of 113 HIV-1 seroconverters from three cohorts for binding to a panel of gp120 core proteins and their corresponding CD4bs knockout mutants. Among sera collected between 99 and 258 weeks post-HIV-1 infection, 88% contained antibodies to the CD4bs and 47% contained antibodies to resurfaced stabilized core (RSC) probes that react preferentially with broadly neutralizing CD4bs antibodies (BNCD4), such as monoclonal antibodies (MAbs) VRC01 and VRC-CH31.

CAPRISA 004 tenofovir microbicide trial: no impact of tenofovir gel on the HIV transmission bottleneck.

Alterations of the genital mucosal barrier may influence the number of viruses transmitted from a human immunodeficiency virus-infected source host to the newly infected individual. We used heteroduplex tracking assay and single-genome sequencing to investigate the effect of a tenofovir-based microbicide gel on the transmission bottleneck in women who seroconverted during the CAPRISA 004 microbicide trial. Seventy-seven percent (17 of 22; 95% confidence interval [CI], 56%-90%) of women in the tenofovir gel arm were infected with a single virus compared with 92% (13 of 14; 95% CI, 67%->99%) in the placebo arm (P = .

Contraception and pregnancy in microbicide trials.

The distinctive feature of the human immunodeficiency virus (HIV) epidemic in Sub-Saharan Africa is the burden on women, in particular young women of reproductive age. Consequently, most late-phase effectiveness microbicide clinical trials are conducted in sub-Saharan Africa where fertility rates are high. Because late-phase clinical trials are conducted over prolonged periods of time, women participating in these trials may fall pregnant during the trial.

Preservation HIV-1-specific IFNγ+ CD4+ T-cell responses in breakthrough infections after exposure to tenofovir gel in the CAPRISA 004 microbicide trial.

The Centre for the AIDS Program of Research in South Africa 004 trial demonstrated reduction of sexual HIV-1 acquisition in women using a vaginal microbicide containing tenofovir. A better understanding of the consequences of antiretroviral-containing microbicides for immune responses in individuals with intercurrent HIV-1 infection is needed for future trials combining the use of microbicides with HIV-1 vaccines. Investigation of immune responses in women who acquired HIV-1 although using tenofovir gel showed significantly higher (P = 0.

Contraceptive choices, pregnancy rates, and outcomes in a microbicide trial.

Objective: Women who become pregnant during the conduct of biomedical human immunodeficiency virus prevention trials are taken off the study product for safety reasons. High pregnancy rates can compromise statistical integrity in these trials. The comprehensive contraceptive curriculum developed for the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial was evaluated for its ability to enhance contraceptive uptake, reduce pregnancy rates, and preserve statistical integrity.

The neutralization breadth of HIV-1 develops incrementally over four years and is associated with CD4+ T cell decline and high viral load during acute infection.

An understanding of how broadly neutralizing activity develops in HIV-1-infected individuals is needed to guide vaccine design and immunization strategies. Here we used a large panel of 44 HIV-1 envelope variants (subtypes A, B, and C) to evaluate the presence of broadly neutralizing antibodies in serum samples obtained 3 years after seroconversion from 40 women enrolled in the CAPRISA 002 acute infection cohort. Seven of 40 participants had serum antibodies that neutralized more than 40% of viruses tested and were considered to have neutralization breadth.

Recruitment of high risk women for HIV prevention trials: baseline HIV prevalence and sexual behavior in the CAPRISA 004 tenofovir gel trial.

Background: Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use.

Purpose: This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa.

Potent and broad neutralization of HIV-1 subtype C by plasma antibodies targeting a quaternary epitope including residues in the V2 loop.

The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000.

Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women.

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.

Preventing HIV infection in women: a global health imperative.

Women account for approximately one-half of all human immunodeficiency virus (HIV) infections worldwide. Sexual transmission is the dominant mode of HIV transmission to women, and there is a concomitant associated epidemic of transmission to infants. The majority of HIV infections in women are in sub-Saharan Africa, with a disproportionate burden in young women <25 years of age.