HIV-1 infections lead to a progressive depletion of CD4 cells culminating in AIDS. The coreceptor usage by HIV varies from CCR5 (R5) tropic early in infection to CXCR4 (X4) tropic in later infections. Although the coreceptor switch from R5 to X4 tropic HIV is well associated with progression to AIDS, the role of CCR5 in disease progression especially in patients infected exclusively with R5 isolates throughout the disease remains enigmatic. To better understand the role of CCR5 and R5 tropic HIV envelope in AIDS pathogenesis, we asked whether the levels of CCR5 and/or HIV Env-mediated fusion determine apoptosis of bystander cells. We generated CD4 ؉ T cell lines expressing varying levels of CCR5 on the cell surface to show that CCR5 expression levels correlate with bystander apoptosis induction. The mechanism of apoptosis involved caspase-3 activation and mitochondrial depolarization and was dependent on gp41 fusion activity as confirmed by fusion-restricted gp41 point mutants and use of the fusion inhibitor T20. Interestingly, lower levels of CCR5 were able to support virus replication in the absence of bystander apoptosis. Our findings suggest that R5 HIV-1-mediated bystander apoptosis is dependent on both CCR5 expression levels as well as fusogenic activity of the Env glycoprotein.For viral entry, HIV-1 utilizes CD4 as receptor and one of the chemokine receptors as coreceptors, the most common ones being CXCR4 (X4) and CCR5 (R5) (1-3). It is well known that R5 tropic viruses predominate during the initial establishment of infection as they are transmitted with greater efficiency (4 -6), whereas the X4 viruses emerge later during the disease and are associated with rapid progression to AIDS (7,8). The progressive increase in virulence in vivo during the late stages of disease is attributed in many cases to a coreceptor switch from CCR5 tropic to CXCR4 tropic HIV (9 -11). Although in approximately half of the HIV infections the virus switches coreceptor usage to CXCR4, and there are several hypotheses to explain this phenomenon (12-15), the mechanism by which R5 tropic HIV isolates lead to AIDS remains poorly defined especially in patients that remain solely infected with R5 isolates throughout the disease.Although HIV selectively infects CD4 ϩ cells, the relatively few infected cells in vivo do not account for the extensive depletion of CD4 cells. This has led to the idea that the virus is able to kill uninfected bystander CD4 ϩ cells (16) (24,25). In support of this observation, we and others showed that the fusion process mediated by the gp41 subunit of HIV envelope may be critical in bystander killing (26 -28). Furthermore, through mutagenesis studies, we demonstrated that hemifusion (incomplete fusion accompanied by partial mixing of apposing cell membranes) induced by gp41 subunit is the major mechanism for HIV Env-mediated bystander T cell apoptosis (29). The fusion of biological membranes mediated by HIV Env, specifically in the case of R5 tropic viruses, is dependent on the expression level of CCR5 cor...

Gastric cancer, a malignant and highly proliferative condition, has significantly affected a large population around the globe and is known to be caused by various factors including genetic, epigenetic, and environmental influences. Though the global trend of these cancers is declining, an increase in its frequency is still a threat because of changing lifestyles and dietary habits. However, genetic and epigenetic alterations related to gastric cancers also have an equivalent contribution towards carcinogenic development. DNA methylation is one of the major forms of epigenetic modification which plays a significant role in gastric carcinogenesis. Methylation leads to inactivation of some of the most important genes like DNA repair genes, cell cycle regulators, apoptotic genes, transcriptional regulators, and signalling pathway regulators; which subsequently cause uncontrolled proliferation of cells. Mutations in these genes can be used as suitable prognostic markers for early diagnosis of the disease, since late diagnosis of gastric cancers has a huge negative impact on overall patient survival. In this review, we focus on the important epigenetic mutations that contribute to the development of gastric cancer and the molecular pathogenesis underlying each of them. Methylation, acetylation, and histone modifications play an integral role in the onset of genomic instability, one of the many contributory factors to gastric cancer. This article also covers the constraints of incomplete knowledge of epigenetic factors influencing gastric cancer, thus throwing light on our understanding of the disease.

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Socially disadvantaged individuals with HIV experience unacceptably high rates of AIDS and death. The authors developed an adversity index to quantify the impact of demographic and psychosocial factors on HIV care. This retrospective cohort study included 431 participants with HIV on combined antiretroviral therapy between 2000 and 2005. Poor outcome was defined as progression to AIDS, death, virologic failure, or CD4 < 200 cells/µl at six months. The index utilized eight demographic and psychosocial variables independently associated with poor outcome. Exposure to higher numbers of variables in the adversity index significantly increased the rates of poor outcome from 14% (exposure to no variables) to 100% (exposure to seven variables). The odds of poor outcome decreased but remained significant after adjusting for adherence-defining variables, indicating a possible mediating effect of poor adherence. Durably effective therapeutic strategies must include addressing adverse demographic and psychosocial factors affecting people living with HIV.

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