IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4+ T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4+ T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4+ T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4+ T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21–producing HIV-specific, but not human CMV-specific, Ag-experienced CD4+ T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4+ T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.

Human papillomavirus DNA was detected in 32 (11.2%) of 287 individuals. Associated with oral human papillomavirus infection on univariate analyses were human immunodeficiency virus infection (odds ratio, 6.9; 95% confidence interval, 2.0-23.2), homosexuality (odds ratio, 3.7; 95% confidence interval, 1.5-9.4), unprotected oral sex (odds ratio, 5.5; 95% confidence interval, 1.6-18.4), syphilis (odds ratio, 2.5; 95% confidence interval, 1.1-6.3), gonorrhea (odds ratio, 4.2; 95% confidence interval, 1.9-9.1), Chlamydia trachomatis (odds ratio, 4.4; 95% confidence interval, 1.8-10.6), and genital herpes (odds ratio, 2.9; 95% confidence interval, 1.3-6.5). Human immunodeficiency virus infection and C. trachomatis were independently predictive of human papillomavirus infection in multivariate stepwise logistic regression.

Originally identified as the gamma interferon-inducing factor, interleukin-18 (IL-18

IL-21 is a relatively newly discovered multifunctional and pleiotropic cytokine. It is produced primarily by CD4(+) T cells, the principal targets of the virus, and therefore this cytokine has special relevance to HIV infection. Here we show for the first time that serum levels of this cytokine are significantly reduced in HIV-infected AIDS patients and correlate significantly with their CD4(+) T-cell counts. These data suggest that the cytokine levels could act as a valuable biomarker for the progression of AIDS.

Progressive multifocal leukoencephalopathy (PML) is usually a fatal neurological disease. The natural history of PML in patients with human immunodeficiency virus infection was analyzed. The correlations between CD4+ lymphocyte count, previous diagnosis of AIDS, treatment with cytarabine, and survival time are reported for 28 individuals for whom the diagnosis of PML was confirmed by histopathologic examination. For 16 patients (57%), PML was the AIDS-defining illness. For these 16 patients, the mean (+/- SD) survival time after presentation was 7.5 +/- 7.6 months (range, 1-31 months), whereas that for the 12 patients (43%) for whom AIDS was previously diagnosed was 3.2 +/- 2.8 months (range, 1-11 months) (P = .01). The overall mean (+/- SD) CD4+ cell count was 85 +/- 82/mm3 (range, 12-349/mm3). The mean (+/- SD) survival time for patients with CD4+ cell counts of > or = 90/mm3 at the time of presentation was 9.4 +/- 8.7 months, while that for patients with CD4+ cell counts of < 90/mm3 at the time of presentation was 3.6 +/- 1.8 months (P = .03). The nine patients did not benefit from treatment with cytarabine.

The cytomegalovirus (CMV) DNA load was determined in polymorphonuclear leukocytes (PMNL) and plasma samples from 106 human immunodeficiency virus-infected subjects at risk of developing CMV disease (group 1) and from 27 AIDS patients with documented CMV disease (group 2). For both groups, the number of CMV copies in PMNL was significantly higher than in plasma when results were derived from an equivalent blood volume (P < .001, PMNL vs. plasma). Additionally, group 2 (symptomatic) patients had a greater viral DNA load than group 1 (asymptomatic) subjects (P < .001 for both PMNL and plasma). The sensitivity, specificity, and positive and negative predictive values of qualitative polymerase chain reaction using PMNL (PCR-PMNL) for the presence of CMV disease were 100%, 58%, 38%, and 100%, respectively, compared with 70%, 93%, 74%, and 92% for qualitative PCR-plasma and 93%, 92%, 76%, and 98% for quantitative PCR-PMNL using a cutoff of 16,000 copies/mL. Thus, the best strategy for diagnosing CMV disease in these individuals relies on quantitative assessment of the viral DNA load in PMNL.

The natural killer (NK) cells play an important role in viral infections via their spontaneous cytolytic activity against virus-infected cells as well as via secreting a variety of soluble mediators. The MHC class I-binding NK receptors of these cells have emerged as the most important regulators of the effector activities of cytolytic cells (both NK and CTL). We have studied the modulation of NK activity and the expression of NK receptors in HIV-infected/AIDS patients and report here that the NK activities of the patients with the lowest plasma HIV load were minimal and vice versa, suggesting a decrease in this activity following suppression of HIV replication. Interestingly, the NK activity correlated negatively with the peripheral blood CD4+ T-cell counts of these patients. Furthermore, these patients showed decreased percentages of CD56+ cells expressing NK receptors of the immunoglobulin superfamily, whereas the percentages of CD8+ cells expressing these receptors were increased. Moreover, the expression of C-type lectin-like NK receptor-associated invariant molecule CD94 was increased on CD8+ cells in these patients as compared with HIV-seronegative controls. These changes in the expression of NK receptors were also evident within groups of these patients having different viral loads. These results show, for the first time, decreased innate immunity and changes in the expression of NK receptors on cytolytic cells in relation to viral burden in HIV-infected/AIDS patient.

Using our gp120/41-expressing, NK cell activity-resistant CEM.NKR cell clones as targets in HIV-1-specific antibody-dependent cellular cytotoxicity (ADCC) assays, we demonstrate here that the serum titers of anti-HIV-1 ADCC antibodies bear a significant (P < 0.05) positive correlation with the peripheral blood CD4+ T cell counts and a negative one with the number of copies of HIV-1 RNA in the plasma of HIV-infected individuals. These findings underscore the importance of these antibodies as a protective immune parameter in these infections.