Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8+ cytotoxic T lymphocyte responses

Abstract

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 influencing the frequency and severity of HSV reactivation in HIV+ patients. Studies to reconstitute such immunity, especially in people with acyclovir-resistant HSV, appear warranted.

Figure 1

Impaired HSV-specific pCTL and pProlif responses in HIV+ individuals. The HSV-specific pCTL frequency per million CD8s from PBMC (A) and the HSV-specific pProlif frequency per million PBMC (B) were measured in individuals who were HSV-seronegative and HIV− (HSV-HIV−), HSV-seropositive and HIV− (HSV+HIV−), or HSV-seropositive and HIV-positive (HSV+HIV+). The median precursor frequency in each group of individuals is displayed. pCTL data for HSV-HIV− and HSV+HIV− are from ref. .

Figure 2

HSV-specific pCTL and pProlif frequencies positively correlate with CD4⁺ and not CD8⁺ lymphocyte counts. pCTL and pProlif frequencies were plotted against absolute CD4⁺ (A and C) and CD8⁺ (B and D) lymphocyte counts. pCTL and pProlif frequencies are displayed as number of precursors per million CD8s (pCTL) or million PBMC (pProlif). Error bars represent the 95% confidence interval of pCTL and pProlif frequencies.

Figure 3

The role of feeders and stimulators in generating HSV-specific pCTL and pProlif responses in an HIV+ individual. The frequency of HSV-specific pCTL (f) in patient T was measured (A) using autologous HSV blasts and irradiated PBMC (T blasts/feeders) or HSV blasts and irradiated PBMC from patient U (U blasts/feeders). Similarly, the frequency of HSV-specific pProlif in patient T was measured (B) using autologous irradiated PBMC as APC (T feeders/APC) or cells from patient U (U feeders/APC).