Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2–4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans.

e Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are essential components in first-line therapy for human immunodeficiency virus (HIV) infection. However, long-term treatment with existing NRTIs can be associated with significant toxic side effects and the emergence of drug-resistant strains. The identification of new NRTIs for the continued management of HIVinfected people therefore is paramount. In this report, we describe the response of a primary isolate of simian immunodeficiency virus (SIV) to 4=-ethynyl-2-fluoro-2=-deoxyadenosine (EFdA) both in vitro and in vivo. EFdA was 3 orders of magnitude better than tenofovir (TFV), zidovudine (AZT), and emtricitabine (FTC) in blocking replication of SIV in monkey peripheral blood mononuclear cells (PBMCs) in vitro, and in a preliminary study using two SIV-infected macaques with advanced AIDS, it was highly effective at treating SIV infection and AIDS symptoms in vivo. Both animals had 3-to 4-log decreases in plasma virus burden within 1 week of EFdA therapy (0.4 mg/kg of body weight, delivered subcutaneously twice a day) that eventually became undetectable. Clinical signs of disease (diarrhea, weight loss, and poor activity) also resolved within the first month of treatment. No detectable clinical or pathological signs of drug toxicity were observed within 6 months of continuous therapy. Virus suppression was sustained until drug treatment was discontinued, at which time virus levels rebounded. Although the rebound virus contained the M184V/I mutation in the viral reverse transcriptase, EFdA was fully effective in maintaining suppression of mutant virus throughout the drug treatment period. These results suggest that expanded studies with EFdA are warranted. N ucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) have proven highly effective in both the treatment of chronic human immunodeficiency virus (HIV) infection (11) and, more recently, as a promising microbicidal prevention strategy for sexually transmitted virus (12). There are seven NRTIs approved for current clinical use, including the nucleoside emtricitabine (FTC) and the nucleotide tenofovir (TFV). Unfortunately, the frequent use of these drugs has resulted in the emergence of resistant virus strains (7,8,10,18). New compounds with potent activity on a wide range of isolates, including NRTI-resistant strains, are critically needed.We and others have previously described a group of 4=-substituted NRTIs that are more potent and have higher selectivity indices in vitro than existing NRTIs (9,13,14,15,16,17). One of the most potent of these compounds, 4=-ethynyl-2-fluoro-2=de-oxyadenosine (EFdA), inhibits HIV-1 replication in primary peripheral blood mononuclear cells (PBMC) with a 50% effective concentration (EC 50 ) of 50 pM, a potency 4 orders of magnitude greater than that of TFV and 400-fold greater than that of AZT (15). It is also nontoxic in vitro at concentrations as high as 10 M, which results in an in vitro selectivity index greater than 200,000. Furthermore, EFdA retains...

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Objectives Chronic obstructive pulmonary disease (COPD) is more prevalent in HIV-infected individuals and is associated with persistent inflammation. Therapies unique to HIV are lacking. We performed a pilot study of the HMG Co-A reductase inhibitor rosuvastatin to determine effects on lung function. Design Randomized, placebo-controlled, triple-blinded trial. Methods HIV-infected individuals with abnormal lung function were recruited from an ongoing lung function study. Participants were randomized to 24 weeks of placebo (n=11) or rosuvastatin (n=11) using an adaptive randomization based on change in peripheral C-reactive protein levels at 30 days of treatment. Forced expiratory volume in one second (FEV1) and diffusing capacity for carbon monoxide (DLco) %-predicted were compared to baseline at 24 weeks in the two groups using Wilcoxon rank-sum. %-predicted change at 24 weeks in pulmonary function variables was compared between groups using simulated randomization tests. Results The placebo group experienced a significant decline in FEV1%-predicted (p=0.027), and no change in DLco%-predicted over 24 weeks. In contrast, FEV1%-predicted remained stable in the rosuvastatin group, and DLco%-predicted increased significantly (p=0.027). There was no significant difference in absolute change in either measure between placebo and rosuvastatin groups. Conclusion In a pilot study, use of rosuvastatin for 24 weeks appeared to slow worsening of airflow obstruction and to improve DLco in HIV-infected individuals with abnormal lung function, although comparison of absolute changes between the groups did not reach significance. This study is the first to test a therapy for COPD in an HIV-infected population, and large-scale clinical trials are needed.