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Severe Genital Herpes Infections in HIV-Infected Individuals with Impaired Herpes Simplex Virus-Specific CD8؉ Cytotoxic T Lymphocyte Responses

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Severe Genital Herpes Infections in HIV-Infected Individuals with Impaired Herpes Simplex Virus-Specific CD8؉ Cytotoxic T Lymphocyte Responses Proc. Natl. Acad. Sci. USA Vol. 94, pp. 10289–10294, September 1997 Immunology Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD81 cytotoxic T lymphocyte responses CHRISTINE M. POSAVAD*, DAVID M. KOELLE*†‡,MARY F. SHAUGHNESSY*, AND LAWRENCE COREY*†‡§ Departments of *Laboratory Medicine and †Medicine, University of Washington, Seattle, WA 98195, and ‡Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, 1124 Columbia Street, Room M115, Seattle, WA 98104 Edited by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved July 16, 1997 (received for review June 9, 1997) ABSTRACT The specific mechanisms underlying the var- The mechanism(s) involved in the worsening of HSV disease ied susceptibility of HIV-infected (HIV1) individuals to op- in HIV1 individuals is not known. Because individuals with portunistic infections (OI) are still incompletely understood. depressed T cell function suffer more serious HSV-related One hypothesis is that quantitative differences in specific T illnesses than immunocompetent individuals or patients with cell responses to a colonizing organism determine the devel- Ig defects, the cellular arm of the adaptive immune system has opment of an AIDS-defining OI. We evaluated this hypothesis long been implicated in preventing and resolving HSV reac- 1 1 for herpes simplex virus (HSV) infection, a common OI in tivations. Although CD4 and CD8 T cells specific for HSV HIV1 patients. Using limiting dilution analyses, the fre- are present in blood (11–16) and in genital herpes lesions (17, 18), the relative importance of HSV-specific cellular immune quency of HSV-specific CD81 cytotoxic T lymphocyte precur- responses compared with other components of the immune sors (pCTL) and proliferative precursors were quantitated in response in controlling HSV disease expression is unclear. peripheral blood mononuclear cells from 20 patients coin- HIV infection and subsequent immunosuppression in individ- fected with HIV and HSV-2. The frequency of HSV-specific uals provide a unique model system to study critical immune 1 CD8 pCTL in HSV1HIV1 individuals was significantly functions necessary for control and resolution of human HSV lower than in HSV1HIV2 individuals (1 in 77,000 vs. 1 in infections. In addition, the study of HSV-specific immune 6,000, P 5 .0005) and was not different than in HSV-HIV2 responses in HIV1 individuals provides an opportunity to individuals (1 in 100,000, P 5 .24). HIV1 patients who study the mechanisms involved in the emergence of a clinically suffered more severe genital herpes recurrences had signifi- relevant OI. Many OIs among HIV1 patients are related to cantly lower HSV-specific CD81 pCTL frequencies than those ubiquitous colonizing agents. Yet even with severe immuno- patients with mild recurrences (1 in 170,000 vs. 1 in 26,000, suppression, clinical disease is seen in only 15–30% of HIV1 P 5 .03). In contrast, no significant difference was seen in individuals. The mechanisms underlying what determines the proliferative precursor frequencies between those patients development of an OI in HIV1 individuals are unclear. with mild vs. severe genital herpes (1 in 3,800 vs. 1 in 6,600, Several studies have demonstrated that HIV1 individuals P > .5). Quantitative differences in pCTL frequency to HSV have significantly lower HSV-specific proliferative responses appear to be the most important host factor influencing the compared to HIV2, HSV-seropositive patients (19, 20). This observation has been correlated with absolute CD41 lympho- frequency and severity of HSV reactivation in HIV1 patients. cyte counts (19, 21). Cytotoxic T lymphocyte (CTL) responses Studies to reconstitute such immunity, especially in people have been shown to be critical in the control of HIV-1 with acyclovir-resistant HSV, appear warranted. replication. However, no studies evaluating the relationship between CTL responses and the development of an OI have Herpes simplex virus 2 (HSV-2) infection is a significant been reported. opportunistic infection (OI) in HIV-infected (HIV1) individ- Therefore, the goal of this study was to determine if there uals, often resulting in frequent reactivation of latent HSV-2 were quantitative differences in cellular immune responses to and severe, long-lasting genital lesions. It is estimated that HSV in HIV1 individuals compared with HIV2 individuals. 50–90% of HIV1 individuals are coinfected with HSV-2 More importantly, were HSV-specific immune responses compared with approximately 20% of HIV-negative (HIV2) quantitatively different between HIV1 patients with severe individuals (1–3). The prevalence of HSV-2 shedding is 4–5 and frequent genital herpes infections vs. HIV1 individuals with mild HSV disease? Using limiting dilution analysis, we times greater in HIV1 individuals than in HIV2 individuals 1 (4), likely increasing HSV transmission. Genital HSV reacti- measured the frequency of HSV-specific CD8 CTL memory precursors (pCTL) and proliferative precursors (pProlif) in a vations have been implicated in increasing the efficiency of cross-sectional study of 20 HIV1 patients with varying severity HIV transmission (5, 6) and in up-regulating HIV replication of HSV disease. 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 MATERIALS AND METHODS infection in HIV1 individuals (8–10). Thus, the high sero- Patients. We studied 20 HIV1 individuals coinfected with prevalence of HSV-2, the high rate of HSV-2 shedding and HSV-2 (16 of whom also were infected with HSV-1) and 14 frequent HSV disease, the presence of HIV in herpetic lesions, and the increase in acyclovir-resistant HSV strains make HSV This paper was submitted directly (Track II) to the Proceedings office. infection a major health problem for HIV1 individuals. Abbreviations: HIV-infected, HIV1; CTL, cytotoxic T lymphocyte; pCTL, cytotoxic T lymphocyte precursor; pProlif, proliferative pre- The publication costs of this article were defrayed in part by page charge cursor; HSV-2, herpes simplex virus 2; OI, opportunistic infection; PBMC, peripheral blood mononuclear cells; PHA, phytohemaggluti- payment. This article must therefore be hereby marked ‘‘advertisement’’ in nin; SI, stimulation indices; EBV, Epstein–Barr virus; APC, antigen- accordance with 18 U.S.C. §1734 solely to indicate this fact. presenting cells. © 1997 by The National Academy of Sciences 0027-8424y97y9410289-6$2.00y0 §To whom reprint requests should be addressed. e-mail: lcorey@ PNAS is available online at http:yywww.pnas.org. u.washington.edu. 10289 Downloaded by guest on September 28, 2021 10290 Immunology: Posavad et al. Proc. Natl. Acad. Sci. USA 94 (1997) immunocompetent people with genital HSV-2. Patients were release). The percent specific 51Cr release was calculated as enrolled into a University of Washington Institutional Review follows: [(cpm experimental release-cpm spontaneous re- Board-approved protocol of the natural history of recurrent lease)y(cpm maximum release - cpm spontaneous release)] 3 genital herpes. Patients were given diary cards to record the 100%. The spontaneous release was always less than 30% of frequency and duration of their genital lesions. Patients were the maximum release. A well was scored as positive if the seen during their genital recurrences and at 6- to 8-week radioactivity in the experimental well was greater than 6% intervals at which time standardized interviews eliciting the specific 51Cr release. Precursor frequencies were calculated by severity and duration of their genital recurrences were re- the x2 minimization method (23) with a computer program corded. At the end of the follow-up (6–12 months), one of the (12) written by L. Sirinek (provided by C. Orosz, both Ohio authors (M.S.) classified the severity of patients’ genital herpes State University, Columbus, OH). into five categories: 0, no recurrences; 11, mild (,6 recur- Lymphoproliferation Assays. PBMC (1 3 105) were incu- rencesyyr, minimum symptoms lasting 3–4 days); 21, moder- bated in triplicate in 200 ml RPMI-H in 96-well round- ate (,6 recurrencesyyr, mean duration of recurrences 3–10 bottomed plates with 1:500 dilution of UV-inactivated HSV-2 days); 31, frequent (.6 recurrencesyyr, mean duration of (HSV-Ag), mock Ag, or PHA-P (0.4 mgyml). After 5 days, 1 recurrences of 3–10 days); and 41, long and frequent (duration mCi [3H]thymidine (New England Nuclear) was added to each of recurrence lasting .10 days andyor .6 recurrencesyyr). well for 18 hr, and its incorporation into DNA was measured. Five additional patients who were seronegative for HSV-1, Stimulation indices (SI) were calculated as follows: cpm HSV- HSV-2, and HIV2 were included as controls. All the labora- Agycpm (mock Ag). Dcpm were calculated by subtracting cpm tory work was performed without knowledge of the clinical from mock Ag wells from cpm from HSV-Ag wells. data. The PBMC precursor frequency of HSV-specific prolifera- Cell Lines. Peripheral blood mononuclear cells (PBMC) tive responses (pProlif frequency) was performed as previously were isolated from peripheral blood by FicollyHypaque den- described (17). Briefly, limiting dilution analysis was per- sity gradient centrifugation and cryopreserved for use as formed by plating PBMC in seven serial 2-fold dilutions stimulator cells, responder cells, or feeder cells. Epstein–Barr starting at 5 3 104 PBMCywell (HIV2, HSV-seropositive virus (EBV)-transformed lymphoblastoid cell lines were pre- people) or 1 3 105 PBMCywell (HSV-seronegative and HIV1 pared from PBMC as previously described (22). Lymphoblas- people) in 24 replicates per dilution in 96-well round-bottomed toid cell line and K562 cells were maintained in RPMI-F culture plates. Autologous irradiated PBMC (2.5 3 104ywell) [RPMI 1640 medium containing 10% fetal bovine serum, 50 and a 1:500 dilution of HSV-Ag were added to each well. mg of streptomycin per ml, 50 units of penicillin per ml, 2 3 Twelve control wells were set up as above but replacing 1025 M 2-mercaptoethanol, 1 mM pyruvate, 2 mM L- HSV-Ag with mock Ag.
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