In an effort to dissect the genetic components of longevity, we have undertaken case-control studies of populations of centenarians (n = 338) and adults aged 20-70 years at several polymorphic candidate gene loci. Here we report results on two genes, chosen for their impact on cardiovascular risk, encoding apolipoprotein E (ApoE), angiotensin-converting enzyme (ACE). We find that the epsilon 4 allele of APOE, which promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls (p < 0.001), while the frequency of the epsilon 2 allele, associated previously with type III and IV hyperlipidemia, is significantly increased (p < 0.01). A variant of ACE which predisposes to coronary heart disease is surprisingly more frequent in centenarians, with a significant increase of the homozygous genotype (p < 0.01). These associations provide examples of genetic influences on differential survival and may point to pleiotropic age-dependent effects on longevity.

To elucidate the genetic factors predisposing to AIDS progression, we analyzed a unique cohort of 275 human immunodeficiency virus (HIV) type 1-seropositive nonprogressor patients in relation to a control group of 1352 seronegative individuals in a genomewide association study (GWAS). The strongest association was obtained for HCP5 rs2395029 (P=6.79x10(-10); odds ratio, 3.47) and was possibly linked to an effect of sex. Interestingly, this single-nucleotide polymorphism (SNP) was in high linkage disequilibrium with HLA-B, MICB, TNF, and several other HLA locus SNPs and haplotypes. A meta-analysis of our genomic data combined with data from the previously conducted Euro-CHAVI (Center for HIV/AIDS Vaccine Immunology) GWAS confirmed the HCP5 signal (P=3.02x10(-19)) and identified several new associations, all of them involving HLA genes: MICB, TNF, RDBP, BAT1-5, PSORS1C1, and HLA-C. Finally, stratification by HCP5 rs2395029 genotypes emphasized an independent role for ZNRD1, also in the HLA locus, and this finding was confirmed by experimental data. The present study, the first GWAS of HIV-1 nonprogressors, underscores the potential for some HLA genes to control disease progression soon after infection.

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Human Herpes virus‐6 (HHV‐6) can co‐infect with HIV‐1 human CD4+ T‐cells, leading to accelerated cell death, and factors in HHV‐6‐infected cells stimulate HIV‐1 LTR directed gene expression. In this study, we have examined the mechanism of HIV‐1 activation by HHV‐6 and localized the cis‐acting sequences of HIV‐1 LTR responsive to trans‐activation. Increased HIV‐1 LTR directed gene expression is obtained in HIV‐1 infected cells co‐infected with HHV‐6, or in HHV‐6 infected cells co‐transfected with the HIV‐1 tat gene. Parallel increases of HIV‐1‐specific transcripts are seen by in situ hybridization in HHV‐6/HIV‐1 doubly infected cells as compared to single HIV‐1 infection. Similarly, infection by HHV‐6 increases the steady‐state level of HIV‐1 LTR mRNA that parallels CAT enzymatic activity, suggesting a transcriptional and/or post‐transcriptional activation. Sequences necessary for HIV‐1 LTR activation by HHV‐6 are distinct from those required for that tat response and map to a region of the HIV‐1 LTR from ‐103 to ‐48. The HIV‐1 enhancer sequence (‐105 to ‐80) is sufficient to confer HHV‐6 inducibility to a heterologous promoter, and nuclear protein(s) activated or induced by HHV‐6 infection specifically bind to the NF kappa B motifs of the HIV‐1 enhancer region.(ABSTRACT TRUNCATED AT 250 WORDS)

The statistical and biological relevance of these associations and their high ORs underscore the power of extreme phenotypes for GWASs, even with a modest sample size. These genetic results emphasize the role of the transforming growth factor beta pathway in the pathogenesis of HIV-1 disease. Finally, the wealth of information provided by this study should help unravel new diagnostic and therapeutic targets.

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The human B-lymphotropic virus (HBLV) has a double-stranded DNA genome of greater than 110 kilobase pairs, which is consistent with its morphological classification as a herpesvirus. A 9000-base pair cloned probe of HBLV detected specific sequences in DNA and RNA of infected cells but did not hybridize to the genomic DNA of other human herpesviruses including the Epstein-Barr virus, human cytomegalovirus, herpes simplex type I, and varicella-zoster virus. Conversely, while probes obtained from each of the known human herpesvirus readily detected the homologous viral DNA, they did not hybridize to genomic HBLV DNA. This evidence, in addition to serological and morphological distinctions and the biological effects of this virus demonstrate that HBLV is a novel human herpesvirus.