No abstract

In early trials of antiretroviral therapy, acyclovir was associated with increased survival by an unknown mechanism. The hypothesis that subclinical herpes simplex virus (HSV) reactivation was associated, in vivo, with increased plasma human immunodeficiency virus (HIV) RNA and suppression with a reduced plasma HIV RNA load was investigated. HSV cultures were performed daily on HSV-2-positive/HIV-positive patients, and plasma HIV-1 RNA loads were measured at regular intervals. A subset of patients prior to, during, and after HSV suppression with high-dose acyclovir was measured to determine whether HSV suppression was associated with a decrease in HIV replication. Most (25/27 HSV-2-positive/HIV-positive persons) reactivated HSV. Total HSV shedding rate was strongly correlated with plasma HIV-1 RNA load (R=0.54; P=.004), and the plasma HIV-1 RNA level at a given CD4 cell count was 48% lower when treated with acyclovir. These data indicate that frequent mucosal HSV reactivation influences HIV replication in vivo and daily HSV suppression may be important in the management of HSV-positive/HIV-positive persons.

The specific mechanisms underlying the varied susceptibility of HIV-infected (HIV؉) individuals to opportunistic infections (OI) are still incompletely understood. One hypothesis is that quantitative differences in specific T cell responses to a colonizing organism determine the development of an AIDS-defining OI. We evaluated this hypothesis for herpes simplex virus (HSV) infection, a common OI in HIV؉ patients. Using limiting dilution analyses, the frequency of HSV-specific CD8 ؉ cytotoxic T lymphocyte precursors (pCTL) and proliferative precursors were quantitated in peripheral blood mononuclear cells from 20 patients coinfected with HIV and HSV-2. The frequency of HSV-specific CD8 ؉ pCTL in HSV؉HIV؉ individuals was significantly lower than in HSV؉HIV؊ individuals (1 in 77,000 vs. 1 in 6,000, P ‫؍‬ .0005) and was not different than in HSV-HIV؊ individuals (1 in 100,000, P ‫؍‬ .24). HIV؉ patients who suffered more severe genital herpes recurrences had significantly lower HSV-specific CD8 ؉ pCTL frequencies than those patients with mild recurrences (1 in 170,000 vs. 1 in 26,000, P ‫؍‬ .03). In contrast, no significant difference was seen in proliferative precursor frequencies between those patients with mild vs. severe genital herpes (1 in 3,800 vs. 1 in 6,600, P > .5). Quantitative differences in pCTL frequency to HSV appear to be the most important host factor inf luencing the frequency and severity of HSV reactivation in HIV؉ patients. Studies to reconstitute such immunity, especially in people with acyclovir-resistant HSV, appear warranted.Herpes simplex virus 2 (HSV-2) infection is a significant opportunistic infection (OI) in HIV-infected (HIVϩ) individuals, often resulting in frequent reactivation of latent HSV-2 and severe, long-lasting genital lesions. It is estimated that 50-90% of HIVϩ individuals are coinfected with HSV-2 compared with approximately 20% of HIV-negative (HIVϪ) individuals (1-3). The prevalence of HSV-2 shedding is 4-5 times greater in HIVϩ individuals than in HIVϪ individuals (4), likely increasing HSV transmission. Genital HSV reactivations have been implicated in increasing the efficiency of HIV transmission (5, 6) and in up-regulating HIV replication by transactivation of the HIV-long terminal repeat by HSV proteins (7). Moreover, an increase in acyclovir-resistant strains of HSV-2 are complicating the treatment of HSV infection in HIVϩ individuals (8-10). Thus, the high seroprevalence of HSV-2, the high rate of HSV-2 shedding and frequent HSV disease, the presence of HIV in herpetic lesions, and the increase in acyclovir-resistant HSV strains make HSV infection a major health problem for HIVϩ individuals. The mechanism(s) involved in the worsening of HSV disease in HIVϩ individuals is not known. Because individuals with depressed T cell function suffer more serious HSV-related illnesses than immunocompetent individuals or patients with Ig defects, the cellular arm of the adaptive immune system has long been implicated in preventing and resolving HSV reactivations. Althoug...