In this study we date the introduction of HIV-2 into the human population and estimate the epidemic history of HIV-2 subtype A in Guinea-Bissau, the putative geographic origin of HIV-2. The evolutionary history of the simian immunodeficiency virus sooty mangabey͞HIV-2 lineage was reconstructed by using available database sequences with known sampling dates, and a timescale for this history was calculated by using maximum likelihood methods. The date of the most recent common ancestor of HIV-2 subtype A strains was estimated to be 1940 ؎ 16 and that of B strains was estimated to be 1945 ؎ 14. In addition we used coalescent theory to estimate the past population dynamics of HIV-2 subtype A in a rural population of Guinea-Bissau. Parametric and nonparametric estimates of the effective number of infections through time were obtained for an equal sample of gag, pol, and env sequences. Our estimates of the epidemic history of HIV-2 subtype A in Guinea-Bissau show a transition from constant size to rapid exponential growth around 1955-1970. Our analysis provides evidence for a zoonotic transfer of HIV-2 during the first half of the 20th century and an epidemic initiation in Guinea-Bissau that coincides with the independence war (1963)(1964)(1965)(1966)(1967)(1968)(1969)(1970)(1971)(1972)(1973)(1974), suggesting that war-related changes in sociocultural patterns had a major impact on the HIV-2 epidemic.T he AIDS epidemic is clearly recognized as a viral zoonosis (1-3). Phylogenetic analysis indicates that multiple interspecies transmissions from simian species have introduced two genetically distinct types of HIV into the human population: HIV-1, closely related to simian immunodeficiency virus (SIV) from chimpanzees (SIV CPZ ), and HIV-2, closely related to SIV from sooty mangabeys (SIV SM ). Whereas HIV-1 group M subtypes (A-D, F, H, J, and K) are spread globally, HIV-2 subtypes are mainly restricted to West Africa and can be categorized as epidemic subtypes (A and B) and nonepidemic subtypes (C-G) (4-7). Biological reasons have been invoked to explain the difference in global epidemiology between HIV-1 and HIV-2, such as lower HIV-2 viral loads that correlate with a lower transmissibility (8-10). However, attempts to compare the history of the epidemics at their respective geographic origins are still lacking.A useful strategy for investigating the epidemic history of HIV combines molecular clock analysis, to estimate the timescale of the epidemic, and coalescent theory, to infer the demographic history of the virus (11). Various molecular clock calculations have dated the most recent common ancestor (MRCA) of HIV-1 group M around 1930 Ϯ 15 (12-14). HIV-1 group M has subsequently spread globally, generating the pandemic observed today. Here, we investigate the epidemic history of HIV-2 to test previously suggested hypotheses of its origin. We provide the first estimated dates of cross-species transmissions of HIV-2. Our results indicate a transfer of HIV-2 subtypes A and B from sooty mangabeys to humans during the fi...

Background: CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively.

The severe acute respiratory syndrome (SARS) epidemic of 2003 was responsible for 774 deaths and caused significant economic damage worldwide. Since July 2003, a number of SARS cases have occurred in China, raising the possibility of future epidemics. We describe here a rapid, sensitive, and highly efficient assay for the detection of SARS coronavirus (SARS-CoV) in cultured material and a small number (n ‫؍‬ 7) of clinical samples. Using rolling circle amplification (RCA), we were able to achieve sensitive detection levels of SARS-CoV RNA in both solid and liquid phases. The main advantage of RCA is that it can be performed under isothermal conditions with minimal reagents and avoids the generation of false-positive results, a problem that is frequently encountered in PCR-based assays. Furthermore, the RCA technology provides a faster, more sensitive, and economical option to currently available PCR-based methods.Severe acute respiratory syndrome (SARS) is an emerging disease caused by the novel SARS coronavirus (SARS-CoV) (2,4,5,14). By the end of the SARS epidemic in July 2003, a total of 8,096 SARS cases had been reported from 30 countries, with 774 deaths. Whether future outbreaks of SARS will occur is unknown at present. However, given the recent SARS cases in southern China arising from an unknown source and a number of laboratory-related infections (12), it is important to be prepared for such a possibility. In the absence of a SARSCoV vaccine or antiviral drugs, the use of strict infection control policies and early diagnosis with rapid, sensitive, and highly specific laboratory methods are essential for the early management of SARS-CoV infection.Apart from epidemiological linkages, the clinical and radiographic features of the disease are not SARS specific, identifying a need for specific laboratory tests that can confirm SARS-CoV infection early in the course of the illness. Detection of SARS-CoV-specific antibodies is a sensitive and specific but is not possible at clinical presentation (6,14).Detection of SARS-CoV by reverse transcription-PCR (RT-PCR) in clinical specimens allows diagnosis in the early stage of the disease. However, in contrast to many other acute respiratory infections, only low levels of SARS-CoV are thought to be present during the early symptomatic phase of infection. On the basis of the results of first-generation RT-PCR assays, SARS-CoV RNA can be detected with a sensitivity of only ca. 30 to 50% in a single respiratory specimen. A higher sensitivity can be achieved if serial samples are collected, particularly during the second week of illness when maximal virus shedding occurs (13,14). The type of clinical sample (e.g., nasopharyngeal aspirate, throat swabs, stool samples, urine, etc.) also affects the sensitivity of .Recently, the utility of circularizable oligonucleotides, or "padlock probes," has been demonstrated for the detection of target nucleic acid sequences; this approach shows greater sensitivity than conventional PCR (3,8,16). Upon hybridization to a target DNA or...

These data suggest that nef/U3 miRNAs produced in HIV-1-infected cells may suppress both Nef function and HIV-1 virulence through the RNAi pathway.

AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to be a problem in the era of highly active antiretroviral therapy (HAART). A better understanding of the drug resistance mutation patterns that emerge in the central nervous system (CNS) during HAART is of paramount importance as these differences in drug resistance mutations may explain underlying reasons for poor penetration of antiretroviral drugs into the CNS and suboptimal concentrations of the drugs that may reside in the brains of HIV-infected individuals during therapy. Thus, we provide a detailed analysis of HIV type 1 (HIV-1) protease and reverse transcriptase (RT) genes derived from different regions of the brains of 20 HIV-1-infected patients (5 without ADC, 2 with probable ADC, and 13 with various stages of ADC) on antiretroviral therapy. We show the compartmentalization and independent evolution of both primary and secondary drug resistance mutations to both RT and protease inhibitors in diverse regions of the CNS of HIV-infected patients, with and without dementia, on antiretroviral therapy. Our results suggest that the independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation upon failure of therapy.

After ART, both CD31(+) and CD31⁻ naive CD4(+) T cells expand, and both subsets represent a stable, persistent reservoir of HIV-1.

Neurodegenerative diseases (NDs) are chronic degenerative diseases of the central nervous system (CNS), which affect 37 million people worldwide. As the lifespan increases, the NDs are the fourth leading cause of death in the developed countries and becoming increasingly prevalent in developing countries. Despite considerable research, the underlying mechanisms remain poorly understood. Although the large majority of studies do not show support for the involvement of pathogenic aetiology in classical NDs, a number of emerging studies show support for possible association of viruses with classical neurodegenerative diseases in humans. Space does not permit for extensive details to be discussed here on non-viral-induced neurodegenerative diseases in humans, as they are well described in literature.Viruses induce alterations and degenerations of neurons both directly and indirectly. Their ability to attack the host immune system, regions of nervous tissue implies that they can interfere with the same pathways involved in classical NDs in humans. Supporting this, many similarities between classical NDs and virus-mediated neurodegeneration (non-classical) have been shown at the anatomic, sub-cellular, genomic and proteomic levels suggesting that viruses can explain neurodegenerative disorders mechanistically. The main objective of this review is to provide readers a detailed snapshot of similarities viral and non-viral neurodegenerative diseases share, so that mechanistic pathways of neurodegeneration in human NDs can be clearly understood. Viruses can guide us to unveil these pathways in human NDs. This will further stimulate the birth of new concepts in the biological research, which is needed for gaining deeper insights into the treatment of human NDs and delineate mechanisms underlying neurodegeneration.

HIV-1 subtype C (C-HIV) is responsible for most HIV-1 cases worldwide. Although the pathogenesis of C-HIV is thought to predominantly involve CCR5-restricted (R5) strains, we do not have a firm understanding of how frequently CXCR4-using (X4 and R5X4) variants emerge in subjects with progressive C-HIV infection. Nor do we completely understand the molecular determinants of coreceptor switching by C-HIV variants. Here, we characterized a panel of HIV-1 envelope glycoproteins (Envs) (n = 300) cloned sequentially from plasma of 21 antiretroviral therapy (ART)-naïve subjects who experienced progression from chronic to advanced stages of C-HIV infection, and show that CXCR4-using C-HIV variants emerged in only one individual. Mutagenesis studies and structural models suggest that the evolution of R5 to X4 variants in this subject principally involved acquisition of an “Ile-Gly” insertion in the gp120 V3 loop and replacement of the V3 “Gly-Pro-Gly” crown with a “Gly-Arg-Gly” motif, but that the accumulation of additional gp120 “scaffold” mutations was required for these V3 loop changes to confer functional effects. In this context, either of the V3 loop changes could confer possible transitional R5X4 phenotypes, but when present together they completely abolished CCR5 usage and conferred the X4 phenotype. Our results show that the emergence of CXCR4-using strains is rare in this cohort of untreated individuals with advanced C-HIV infection. In the subject where X4 variants did emerge, alterations in the gp120 V3 loop were necessary but not sufficient to confer CXCR4 usage.