Herpes simplex virus type-2 stimulates HIV-1 replication in cervical tissues: implications for HIV-1 transmission and efficacy of anti-HIV-1 microbicides

Abstract

Herpes Simplex virus Type-2 (HSV-2) increases the risk of HIV-1 acquisition, yet the mechanism for this viral pathogen to regulate the susceptibility of the cervicovaginal mucosa to HIV-1 is virtually unknown. Using ex vivo human ectocervical tissue models, we report greater levels of HIV-1 reverse transcription, DNA integration, RNA expression, and virions release in HIV-1/HSV-2 co-infected tissues compared with HIV-1 only infected tissues (P<0.05). Enhanced HIV-1 replication was associated with increased CD4, CCR5, and CD38 transcription (P<0.05) and increased number of CD4+/CCR5+/CD38+ T cells in HIV-1/HSV-2 co-infected tissues compared with tissues infected with HIV-1 alone. Tenofovir (TFV) 1% gel, the leading microbicide candidate, demonstrated only partial protection against HIV-1, when applied vaginally before and after sexual intercourse. It is possible that mucosal inflammation, in particular that induced by HSV-2 infection, may have decreased TFV efficacy. HSV-2 upregulated the number of HIV-1-infected cells and elevated the concentration of TFV needed to decrease HIV-1 infection. Similarly, only high concentrations of TFV inhibited HSV-2 replication in HIV-1/HSV-2-infected tissues. Thus, HSV-2 co-infection and mucosal immune cell activation should be taken into consideration when designing preventative strategies for sexual transmission of HIV-1.

In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa

“…Although anti-HSV-2 activity was lost at the high gel dilution (1: 300), it may still be evident in vivo against a more physiologically relevant HSV-2 inoculum (35,36). Of note, tenofovir at low concentrations (1 g/ml) was shown to inhibit single infections with HIV-1 BaL and HSV-2, but a higher tenofovir dose (100 g/ml) was required to inhibit infections with both viruses in cochallenge experiments (10).…”

“…In populations like sub-Saharan Africa, where HSV-2 is highly prevalent, nearly half of the HIV-1 infections are attributed to HSV-2 coinfection (7,8). Several HSV-2-induced immunomodulatory effects possibly underlying increased HIV-1 transmission have been described (9)(10)(11). Furthermore, increased HIV-1 reverse transcription, DNA integration, and RNA expression and increased p24 release in ectocervical tissue following cochallenge with HIV-1 BaL and HSV-2 have been reported (10).…”

“…Several HSV-2-induced immunomodulatory effects possibly underlying increased HIV-1 transmission have been described (9)(10)(11). Furthermore, increased HIV-1 reverse transcription, DNA integration, and RNA expression and increased p24 release in ectocervical tissue following cochallenge with HIV-1 BaL and HSV-2 have been reported (10). Thus, it would be beneficial for a microbicide to have potent activity against both viruses.…”

“…The CAPRISA004 study demonstrated that the vaginal 1% tenofovir gel reduced HIV-1 acquisition by 39% and HSV-2 acquisition by 51% (12,13). However, decreased potency of low tenofovir concentrations (1 g/ml) ex vivo against both HIV-1 and HSV-2 in the coinfection scenario (coincident with an increased number of CD4 ϩ CCR5 ϩ CD38 ϩ T cells) was reported (10). The Population Council's candidate microbicide gel, PC-1005, which contains the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150, zinc acetate, and carrageenan (CG), has broad anti-HIV activity independent of clade, tropism, or phenotype and against multidrug-resistant strains or clones containing multiple drug resistance mutations (DRMs) in cell-based assays (14).…”

The Vaginal Acquisition and Dissemination of HIV-1 Infection in a Novel Transgenic Mouse Model Is Facilitated by Coinfection with Herpes Simplex Virus 2 and Is Inhibited by Microbicide Treatment

“…Investigating the molecular and cellular mechanisms underlying the synergistic relationships between HIV-1 and HSV-2 infection has been limited by the absence of an in vivo model to study coinfection with these two viruses. Primary HSV-2 infection creates genital ulcerations that disrupt the epithelial surface and compromise the mucosal barrier; this facilitates HIV-1 passage into the submucosa where it encounters mucosal CD4 ϩ T cells, macrophages, and dendritic cells, infects initial target cells, and forms local foci of infected cells which disseminate through-out the lymphoid tissue (10)(11)(12)(13). In addition, HSV-2 infection alters the mucosal microenvironment by increasing the local production of proinflammatory cytokines and chemokines that recruit and activate CD4 ϩ T lymphocytes, macrophages, and dendritic cells, thereby enhancing the probability that HIV-1 will encounter and infect target cells (14)(15)(16).…”