Association Between the Framingham Risk Score and Carotid Artery Intima-Media Thickness in Patients With Human Immunodeficiency Virus.

Cardiovascular diseases (CVD) are more prevalent among HIV-infected subjects. We examined the associations between carotid artery intima-media thickness (CIMT), conventional CVD risk factors, and HIV-related risk factors among Hispanics with HIV infection. This cross-sectional study involved 96 consecutive HIV patients on stable antiretroviral therapy and without history of CVD in a university-based outpatient clinic who underwent carotid ultrasound evaluation. Increased CIMT was defined as common carotid artery-CIMT values greater than or equal to seventy-fifth percentile for the patient's age, sex, and race/ethnicity based on CIMT nomograms from large population studies. The sample was comprised of 96 Hispanic Americans aged 39.7 ± 11.9, 89% of whom were men, 64% were on a protease inhibitor, and 11% had increased CIMT (95% confidence intervals 5.9% to 19.6%). In univariable analysis, increased CIMT was significantly associated (p <0.05) with older age, metabolic syndrome, intermediate/high Framingham risk score, HIV infection duration ≥5 years, integrase inhibitors, and protease inhibitors. In multivariable analysis, only Framingham risk score (p = 0.009) was independently associated with increased CIMT. The median common carotid artery-CIMT value was significantly greater in patients with intermediate/high compared with those with low Framingham risk score (0.60 vs 0.49 mm; p <0.001). In conclusion, given the significant association between increased CIMT and Framingham risk score, adherence to prevention guidelines to reduce CVD risk factor burden in this population is strongly recommended.

CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis.

CCR5 is the major co-receptor for HIV and polymorphisms in the CCR5 gene as well as promoter region that alter cell surface expression have been associated with disease progression. We determined the relationship between CCR5 promoter polymorphisms and CD4 decline and other immunopathological features like immune activation and CD4+ T cell apoptosis in HIV patients. CCR5 promoter haplotype HHC was significantly associated with higher CD4 counts in patients. The relative promoter activity (RPA) of each haplotype was determined in vitro and combined promoter activity based on both alleles (CRPA) was assigned to each patients. Interestingly, CCR5 CRPA correlated inversely with CD4 counts and CD4:CD8 ratio specifically in viremic patients. In normal individuals, the CRPA correlated with the number of CCR5+ CD4+ T cells in the peripheral blood suggesting an effect on CCR5 expression. In a subset of high viremic patients harboring R5 tropic HIV, there was a strong correlation between CCR5 CRPA and both CD4 counts and CD4 T cell apoptosis. Our study demonstrates that, CCR5 promoter polymorphisms correlate with CD4 T cell loss possibly by regulating CD4 T cell apoptosis in HIV patients. Furthermore, assigning CRPAs to each patient is a new method of translating genotype to phenotype.

HIV-1 Env Glycoprotein Phenotype along with Immune Activation Determines CD4 T Cell Loss in HIV Patients.

The mechanism behind the selective depletion of CD4(+) cells in HIV infections remains undetermined. Although HIV selectively infects CD4(+) cells, the relatively few infected cells in vivo cannot account for the extent of CD4(+) T cell depletion, suggesting indirect or bystander mechanisms. The role of virus replication, Env glycoprotein phenotype, and immune activation (IA) in this bystander phenomenon remains controversial. Using samples derived from HIV-infected patients, we demonstrate that, although IA in both CD4(+) and CD8(+) subsets correlates with CD4 decline, apoptosis in CD4(+) and not CD8(+) cells is associated with disease progression. Because HIV-1 Env glycoprotein has been implicated in bystander apoptosis, we cloned full-length Envs from plasma of viremic patients and tested their apoptosis-inducing potential (AIP). Interestingly, AIP of HIV-1 Env glycoproteins were found to correlate inversely with CD4:CD8 ratios, suggesting a role of Env phenotype in disease progression. In vitro mitogenic stimulation of PBMCs resulted in upregulation of IA markers but failed to alter the CD4:CD8 ratio. However, coculture of normal PBMCs with Env-expressing cells resulted in selective CD4 loss that was significantly enhanced by IA. Our study demonstrates that AIP of HIV-1 Env and IA collectively determine CD4 loss in HIV infection.

Characterization of programmed death-1 homologue-1 (PD-1H) expression and function in normal and HIV infected individuals.

Chronic immune activation that persists despite anti-retroviral therapy (ART) is the strongest predictor of disease progression in HIV infection. Monocyte/macrophages in HIV-infected individuals are known to spontaneously secrete cytokines, although neither the mechanism nor the molecules involved are known. Here we show that overexpression of the newly described co-stimulatory molecule, PD1 homologue (PD-1H) in human monocyte/macrophages is sufficient to induce spontaneous secretion of multiple cytokines. The process requires signaling via PD-1H as cytokine secretion could be abrogated by deletion of the cytoplasmic domain. Such overexpression of PD-1H, associated with spontaneous cytokine expression is seen in monocytes from chronically HIV-infected individuals and this correlates with immune activation and CD4 depletion, but not viral load. Moreover, antigen presentation by PD-1H-overexpressing monocytes results in enhanced cytokine secretion by HIV-specific T cells. These results suggest that PD-1H might play a crucial role in modulating immune activation and immune response in HIV infection.

The epidemiology of HIV/AIDS in Minnesota: current trends.

The epidemic of HIV infection and HIV/AIDS in Minnesota reflects national trends in transmission and progression to disease. Analysis of Minnesota's data also highlights populations that are at much greater risk for HIV infection and progression to AIDS. Although men who have sex with men continue to comprise the majority of people in Minnesota with HIV, other subpopulations--women, people of color, and foreign-born residents--are seeing a rise in their infection rates as well. Members of these groups tend to be diagnosed later and, thus, are at greater risk for their infection to progress to AIDS. This article discusses some of the nuances of the most recent epidemiologic data on HIV/AIDS in Minnesota and makes the case for continued aggressive strategies for outreach, education, and adequate access to health care services among at-risk populations.

Management of HIV: a swing back to the future.

During the last 15 years, there have been numerous advancements in the development of antiretroviral drug therapies for people with HIV/AIDS. More drugs and more classes of drugs are now available to treat the disease, and they have fewer side effects than older therapies. This article provides an overview of the current management guidelines for HIV infection in adults in the United States. It also highlights the rationale behind HIV treatment, including when to start it, what therapies to use, and details about key drugs and regimens.

Peering into the future: searching for answers to old and new questions about HIV/AIDS.

The success of the scientific quest to understand and treat HIV/AIDS since it was first identified in the United States nearly 30 years ago merits celebration; yet new, unexpected problems continue to develop as old ones persist. The significant benefits of combination antiretroviral therapy (cART) have contributed to the perception that the global or national threat posed by HIV/AIDS no longer exists. The persistent high levels of new HIV infections in the United States (56,000/year) and the world (2.7 million/year) underscore how much work remains to be done. This article highlights seven key questions that will define the scientific, clinical, and policy efforts to combat HIV/AIDS in the decades ahead.