Relationship Between T-Cell Responses to CMV, Markers of Inflammation, and Frailty in HIV-uninfected and HIV-infected Men in the Multicenter AIDS Cohort Study.

Background: Both aging and treated human immunodeficiency virus (HIV)-infected populations exhibit low-level chronic immune activation of unknown etiology, which correlates with morbidity and mortality. Cytomegalovirus (CMV) infection is common in both populations, but its relation to immune activation is unknown. Methods: T cells from men who have sex with men (22 virologically suppressed HIV+, 20 HIV-) were stimulated with peptides spanning 19 CMV open reading frames, and intracellular cytokine responses were assessed. Soluble and cellular inflammatory markers were assessed by multiplex electrochemiluminescence and flow cytometry, respectively. Frailty was assessed by the Fried criteria. Results: All men had responses to CMV. Proportions of CMV-responsive T cells correlated strongly (r ≥ 0.6 or ≤ -0.6; P < .05) with immunologic markers, depending on donor HIV and frailty status. Markers significantly correlated in some groups after adjustment for multiple comparisons included interferon-γ, tumor necrosis factor-α, interleukin-6, and several chemokines in serum, and the proportion of activated T cells. The magnitude of the CD4 IL-2 response significantly predicted onset of frailty in HIV- nonfrail men, but not in HIV+ nonfrail men. Conclusions: T-cell responses to CMV may strongly influence chronic immune activation in HIV-uninfected and virologically suppressed HIV-infected men, and may predict frailty in HIV-uninfected men.

Effect of Statin Therapy on Age-Associated Changes in Physical Function Among Men With and Without HIV in the Multicenter AIDS Cohort Study.

BACKGROUND: The longer-term risks of statins on physical function among people with HIV are unclear. METHODS: Longitudinal analysis of Multicenter AIDS Cohort Study men between 40 and 75 years of age with ≥2 measures of gait speed or grip strength. Generalized estimating equations with interaction terms between (1) statin use and age and (2) HIV serostatus, age, and statin use were considered to evaluate associations between statin use and physical function. Models were adjusted for demographics and cardiovascular risk factors. RESULTS: Among 2021 men (1048 with HIV), baseline median age was 52 (interquartile range 46-58) years; 636 were consistent, 398 intermittent, and 987 never statin users. There was a significant interaction between age, statin, and HIV serostatus for gait speed. Among people with HIV, for every 5-year age increase, gait speed (m/s) decline was marginally greater among consistent versus never statin users {-0.008 [95% confidence interval (CI) -0.017 to -0.00007]; P = 0.048}, with more notable differences between intermittent and never users [-0.017 (95% CI -0.027 to -0.008); P < 0.001]. Similar results were observed among men without HIV. Significant differences in grip strength (kg) decline were seen between intermittent and never users [-0.53 (95% CI -0.98 to -0.07); P = 0.024] and differences between consistent and never users [-0.28 (95% CI -0.63 to 0.06); P = 0.11] were not statistically significant. CONCLUSIONS: Among men with and without HIV, intermittent statin users had more pronounced declines in physical function compared with consistent and never users. Consistent statin use does not seem to have a major impact on physical function in men with or without HIV.

Immune activation and IL-12 production during acute/early HIV infection in the absence and presence of highly active, antiretroviral therapy.

Suppressed IL-12 production and maladaptive immune activation, both of which are ameliorated by successful highly active antiretroviral therapy (HAART), are thought to play important roles in the immunopathogenesis of chronic HIV infection. Despite the important effects of the immunological and virological events of early HIV infection on subsequent disease progression, IL-12 production and immune activation in early infection remain under-defined. To quantify IL-12 production and immune activation during acute/early HIV infection, in the presence and absence of HAART, we performed a prospective, longitudinal study of participants in the Baltimore site of the Acute Infection and Early Disease Research Program, with cross-sectional comparison to healthy control subjects. PBMC cytokine productive capacity and plasma immune activation markers [soluble CD8 (sCD8), sCD4, granzyme B, neopterin, beta2-microglobulin, sIL-2R, sTNFRI, sTNFRII, and IL-12p70] were quantified by ELISA. Notably, PBMC from patients with acute/early HIV infection exhibited in vivo IL-12p70 production along with increased, maximal in vitro IL-12 production. Further, despite evidence from plasma markers of generalized immune activation, no elevation in plasma levels of sCD4 was observed, suggesting relative blunting of in vivo CD4+ T cell activation from the beginning of HIV infection. Finally, despite successful virological responses to HAART, heightened in vivo CD8+ T cell activation, IL-12 production, and IFN activity were sustained for at least 6 months during primary HIV infection. These data underscore the need for comparative mechanistic analysis of the immunobiology of early and chronic HIV infection.

High frequency of highly active antiretroviral therapy modifications in patients with acute or early human immunodeficiency virus infection.

STUDY OBJECTIVES: To examine the frequency of highly active antiretroviral therapy (HAART) modifications, the reasons for these modifications, and toxicities of these drugs in patients receiving their first HAART regimen after a diagnosis of acute (< 2 mo from infection) or early (2-12 mo) human immunodeficiency virus (HIV) infection. PATIENTS: Fifty-one patients who were enrolled in the Acute Infection and Early Disease Research Program at a Baltimore, Maryland, site between January 1, 1998, and April 30, 2002, and who chose to start HAART. MEASUREMENTS AND MAIN RESULTS: Time from initiation of therapy to first modification-defined as change in any HAART drug without an interruption in therapy or as simultaneous discontinuation of all drugs within the regimen-and time from initiation of therapy to reinitiation of therapy were recorded, as well as reasons for modification and reinitiation. With a median follow-up of 1,549 days, 21 (41%) of 51 patients received HAART continuously, but only 10 (20%) continued to receive their original regimen without any modification. Among the 41 patients (80%) who received modified therapy, the main reasons for the first modification were toxicity (16 patients), nonadherence (8), and new data on treatment efficacy or safety (8). Of 30 patients who stopped HAART, 18 restarted HAART at a later time. CONCLUSION: The high frequency of treatment modification among patients treated after acute or early HIV infection underscores the importance of determining the usefulness of antiretroviral therapy early in HIV infection, and the need for more tolerable regimens if HAART is to be started at this stage.

HIV-1 Gag evolution in recently infected human leukocyte antigen-B*57 patients with low-level viremia.

We studied viral evolution in five human leukocyte antigen (HLA)-B*57 patients recently infected with HIV-1. Escape mutations in HLA-B*57-restricted Gag epitopes were present at study entry in all patients, but were not associated with significant increases in viremia. Conversely, no new escape mutations in HLA-B*57-restricted epitopes or known compensatory mutations were detected in patients who experienced significant increases in viremia. Thus, the development of escape mutations alone does not determine virologic outcome in recently infected HLA-B*57 patients.

Association of Gag-specific T lymphocyte responses during the early phase of human immunodeficiency virus type 1 infection and lower virus load set point.

T lymphocyte responses to human immunodeficiency virus (HIV) type 1 Gag were measured in 9 patients by interferon-gamma enzyme-linked immunospot assay at 3 time points within 12 months of infection. Patients with early recognition of HIV-1 Gag had lower subsequent HIV-1 load set points, as measured during the first 2 years of infection, compared with those of patients with undetectable Gag-specific responses (median, 4.27 vs. 5.05 log(10) HIV-1 RNA copies/mL, respectively; P=.028). An inverse correlation existed between the magnitude of the Gag-specific responses and the HIV-1 load set point (r=-0.733; P=.025). Early sustained T lymphocyte responses to HIV-1 Gag may be important for the establishment of virus load set point.

Screening for HIV infection in high-risk communities by urine antibody testing.

OBJECTIVES: To evaluate the effectiveness of urine screening to detect HIV-infected individuals in high-prevalence communities. METHODS: Urine HIV testing was performed at 16 discrete events and four ongoing testing sites in Baltimore communities with a high incidence of HIV infection. When possible, positive urine test results were confirmed by blood testing. In addition, we attempted to obtain blood samples from subjects who reported a possible exposure to HIV but did not have a positive urine test. RESULTS: From February 1998 to August 2001, we screened 1718 persons. Overall, 210 persons (12%) were HIV-positive, of whom 169 (80%) had never previously tested positive; 87% of those who tested positive received their results, and most were referred for medical care. CONCLUSIONS: Urine-based screening for HIV infection in high-prevalence inner city communities can be an effective tool for identifying and treating infected persons who are unaware of their infection.