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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry-independent mechanisms.
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PMID:CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms. 1802 77

In the last 10 years HIV-1/human T-cell leukemia virus (HIV-1/HTLV) coinfection has emerged as a worldwide health problem. The numbers of HIV-1/HTLV-1 coinfections in South America and Africa are increasing, as well as HIV-1/HTLV-2 coinfections in the USA and Europe. Coinfections by either HTLV-1 or HTLV-2 and HIV-1 frequently occur in persons with a history of injection drug use. Since HTLV-1 preferentially infects CD4+ T-cells and HTLV-2 has a tropism for CD8+ T-cells, the influence of coinfection on HIV-1 disease progression may be different. The effect of HIV-1/HTLV-1 coinfection on HIV-I pathogenesis is controversial as soluble factors produced by HTLV-1 infected cells can either enhance or suppress HIV-1 infection. In HTLV-1/HIV-1 coinfected patients, upregulation of HIV-1 expression was attributed to strong activation of cytokines that promoted HIV infection. The introduction of HAART has dramatically reduced HIV-1 morbidity and mortality, but has given rise to an increased number of inflammatory syndromes. While HAART is successful for controlling HIV disease, it has little impact on HTLV-1/2 genome expression. The consequence of coinfection, even with HAART, may well be the reported increase in neurologic disease. Several epidemiologic and in vitro studies of the influence of HTLV infection on HIV-1 related AIDS progression suggest that HTLV-1 infection can promote HIV-1 replication and accelerate the clinical progression to AIDS. However, other studies have not confirmed these observations. The differences in study outcomes could be related to the occurrence of different HIV-1 phenotypes in clinical disease. In contrast, evidence points to a confirmed protective role of HTLV-2 that is manifested as improved survival and delayed progression to AIDS. The protective effect may be the result of maintaining normal-range levels of CD4 and CD8 counts, lowering HIV replication, and immune activation. As a corollary, the number of long-term nonprogressors for AIDS in the HIV-1/HTLV-2 coinfected group was found to be significantly higher than in HIV-1 monoinfected cases. Investigations of the natural factors induced by HTLV-2 that influence HIV-1 replication show that CCL3L1 (an isoform of CCL3) is preferentially induced in HTLV-2 exposed seronegative HIV individuals and in long-term nonprogressor HTLV-2/HIV-1 coinfected persons. The CCL3L 1 inhibits HIV replication and thus acts as a potent effector against both HIV infection and disease progression. As a complement to upregulation of CCL3L1, other chemokines and cytokines induced by HTLV-2 may contribute to induction of the Th1 response against invading pathogens, in contrast to the dominant Th2 response that appears to favor HIV infection. The number of individuals with either single HIV-1 or HTLV-2 infection, in a cohort of Italian intravenous drug users monitored for 20 years, decreased significantly over time. However, the magnitude of HTLV-2 decrease was significantly less than that of HIV-1, pointing to the need for increased attention to, and control of, HTLV infection. In conclusion, the long-term effects of HIV and HTLV coinfections are poorly understood and the mechanisms of dysregulation of cellular biosynthesis by HTLV that impact HIV disease progression remain elusive.
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PMID:Molecular and cellular interactions of HIV-1/HTLV coinfection and impact on AIDS progression. 1798 39

The chemokine receptor CCR5 is the most important entry coreceptor for HIV-1 in vivo. Its chemokine ligands, including CCL3L1, efficiently inhibit infection by receptor blockade and downmodulation. However, in Nature Immunology, Dolan et al. (2007) present a large human-cohorts study that identifies entry-independent, CCR5-CCL3L1-dependent effects on cell-mediated immunity as a strong correlate of pathogenesis and point to additional influences of the CCR5-CCL3L1 axis on disease progression through undefined mechanisms.
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PMID:HIV-1 pathogenesis: the complexities of the CCR5-CCL3L1 complex. 1800 46

HIV-specific T-cell responses play an important role in control of infection. Because CCL3 has immune modulatory and antiviral activities, we hypothesized that host CCL3 genotype (CCL3L1 gene duplications) would influence the development of effective HIV-specific immune responses. Copy numbers of CCL3L1 were determined for 71 HIV-infected women, and HIV-specific CD4 and CD8 T-cell responses to overlapping peptide pools spanning the HIV-1 subtype C genome were simultaneously measured by an interferon-gamma and interleukin-2 whole-blood flow cytometric assay. Host CCL3L1 copy number correlated negatively with viral load (r=-0.239, P=0.045), as did magnitudes of Gag CD4 (r=-0.362, P=0.002) and CD8 (r=-0.261, P=0.028) T-cell responses. Patients with a Gag CD4 response (P=0.002) or dominant Gag CD8 (P=0.006) response had significantly lower viral loads than those whose dominant response targeted another region of the genome, whereas a dominant Nef-specific CD8 T-cell response was associated with higher HIV viral load. CCL3L1 copy number greater than or equal to the population median of 5 was significantly associated with increased magnitude of CD4 Gag responses (P=0.017), and women who had CD4 and CD8 Gag-specific responses had significantly lower viral loads (P=0.004) and higher CCL3L1 copy number (P=0.015) than those women with only CD8 Gag-specific responses.
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PMID:Host CCL3L1 gene copy number in relation to HIV-1-specific CD4+ and CD8+ T-cell responses and viral load in South African women. 1836 Feb 85

The basis for the extensive variability seen in the reconstitution of CD4(+) T cell counts in HIV-infected individuals receiving highly active antiretroviral therapy (HAART) is not fully known. Here, we show that variations in CCL3L1 gene dose and CCR5 genotype, but not major histocompatibility complex HLA alleles, influence immune reconstitution, especially when HAART is initiated at <350 CD4(+) T cells/mm(3). The CCL3L1-CCR5 genotypes favoring CD4(+) T cell recovery are similar to those that blunted CD4(+) T cell depletion during the time before HAART became available (pre-HAART era), suggesting that a common CCL3L1-CCR5 genetic pathway regulates the balance between pathogenic and reparative processes from early in the disease course. Hence, CCL3L1-CCR5 variations influence HIV pathogenesis even in the presence of HAART and, therefore, may prospectively identify subjects in whom earlier initiation of therapy is more likely to mitigate immunologic failure despite viral suppression by HAART. Furthermore, as reconstitution of CD4(+) cells during HAART is more sensitive to CCL3L1 dose than to CCR5 genotypes, CCL3L1 analogs might be efficacious in supporting immunological reconstitution.
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PMID:CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. 1981 60

EVALUATION OF: Ahuja SK, Kulkarni H, Catano G et al.: CCL3L1-CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV-1-infected individuals. Nat. Med. 14(4), 413-420 (2008). It is widely accepted that the effect of highly active antiretroviral therapy (HAART) varies widely among HIV-infected individuals. Host genetic factors are thought to be linked to the sensitivity to HAART in HIV-infected individuals. Ahuja et al. attempted to identify the genes that determine the sensitivity to HAART in HIV-infected subjects. Based on the hypothesis that CD4+ depletion and the recovery process in HIV-infected subjects are under the control of specific common genetic pathways, they evaluated the associations of genetic variations, such as CCR5 genotype, CCL3L1 copy number variation and HLA alleles, with the sensitivity to HAART in two cohorts from the USA. They found that the CCL3L1-CCR5 genetic risk status, but not HLA-B*57, is apparently a good predictor of the recovery rate of CD4+ T cells during HAART. In particular, the recovery rate of CD4+ T cells during HAART has the most sensitive association with the copy number of CCL3L1. Furthermore, Ahuja et al. studied the impact of CCL3L1-CCR5 genetic risks in HIV-infected individuals initiating HAART during acute or early infection. They suggested that CCL3L1-CCR5 genetic risk status may be a useful guide in deciding whether to initiate HAART in HIV-infected subjects with a level of 350 CD4+ T cells/mm(3)or more. This study has provided a critical breakthrough in predicting the response to HAART in HIV-infected subjects.
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PMID:Genetic factors that confer sensitivity to HAART in HIV-infected subjects: implication of a benefit of an earlier initiation of HAART. 1878 60

Six allosteric HIV-1 entry inhibitor modulators of the chemokine (C-C motif) receptor 5 (CCR5) receptor are compared for their potency as inhibitors of HIV-1 entry [infection of human osteosarcoma (HOS) cells and peripheral blood mononuclear cells (PBMC)] and antagonists of chemokine (C-C motif) ligand 3-like 1 [CCL3L1]-mediated internalization of CCR5. This latter activity has been identified as a beneficial action of CCL3L1 in prolonging survival after HIV-1 infection ( Science 307: 1434-1440, 2005 ). The allosteric nature of these modulators was further confirmed with the finding of a 58-fold (HOS cells) and 282-fold (PBMC) difference in relative potency for blockade of CCL3L1-mediated internalization versus HIV-1 entry. For the CCR5 modulators, statistically significant differences in this ratio were found for maraviroc, vicriviroc, aplaviroc, Sch-C, TAK652, and TAK779. For instance, although TAK652 is 13-fold more potent as an HIV-1 inhibitor (over blockade of CCL3L1-mediated CCR5 internalization), this ratio of potency is reversed for Sch-C (22-fold more potent for CCR5-mediated internalization over HIV-1 entry). Quantitative analyses of the insurmountable antagonism of CCR5 internalization by these ligands suggest that all of them reduce the efficacy of CCL3L1 for CCR5 internalization. The relatively small magnitude of dextral displacement accompanying the depression of maximal responses for aplaviroc, maraviroc and vicriviroc suggests that these modulators have minimal effects on CCL3L1 affinity, although possible receptor reserve effects obscure complete interpretation of this effect. These data are discussed in terms of the possible benefits of sparing natural CCR5 chemokine function in HIV-1 entry inhibition treatment for AIDS involving allosteric inhibitors.
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PMID:The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property? 1906 29

Interindividual variability in susceptibility to HIV-1 infection, its transmission, disease progression, and response to antiviral therapy has been attributed to host determinants and variability in multiple genes. Although most people exposed to the virus go on to develop full-blown disease at variable intervals, a proportion of them, labeled as long-term nonprogressors or exposed uninfected, possess 'natural resistance' to infection. A better understanding of genetic and immunologic basis of such a natural resistance to infection would bear important implications in designing therapeutic vaccine designs. The genetic variants that could influence susceptibility to HIV-1 and limit AIDS vary in different populations and among individuals. Meta-analyses of large cohort studies have identified numerous 'AIDS restriction genes' that regulate HIV cell entry (particularly chemokine coreceptors and their ligands), acquired and innate immunity (major histocompatibility complex, killer cell immunoglobulin-like receptor, and cytokines), and others [tripartite interaction motif 5 alpha (TRIM5alpha) and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G] that influence outcome of HIV infection. Studies carried out in the Indian population with regard to genetic polymorphisms in chemokine receptors have shown that (i) the protective CCR5 Delta32 variant is rare, (ii) CCR5HHE carrying *59402A is associated with increased likelihood of infection and development of AIDS, and (iii) the Indian population generally has low CCL3L1 copy numbers (approximately 2.3). These data have implications in developing screening tests that could identify people at higher or lower risk of infection and rate of disease progression, predict vaccine responsiveness in clinical trials and understand the pathogenic mechanisms.
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PMID:Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection. 1931 37

The CCR5Delta32 mutation does not account for HIV-1 resistance in the majority of persons who are repeatedly exposed to HIV-1 by high-risk activities but remain seronegative and uninfected. Therefore, we investigated the impact of CCR5 59029 A/G and CCL3L1 copy number polymorphism on HIV-1 disease susceptibility and progression among HIV-1-infected and HIV-1-exposed seronegative North Indians. HIV-1-seropositive (HSP, n = 196) patients, stratified on the basis of disease severity (Stages I, II, and III) and HIV-1-exposed seronegative (HES, n = 47) individuals were genotyped for CCR5-59029 A/G polymorphism by PCR-RFLP and CCL3L1 copy number by the real-time TaqMan PCR method. A group of ethnically matched HIV-1-seronegative (HSN, n = 315) healthy volunteers were also genotyped as controls. Statistical analysis was done by SPSS software. The CCR5-59029 AG genotype was significantly higher in the HES compared with the HSP group (57.44% vs. 37.24%, p = 0.014). The CCL3L1 mean copy number of HES was higher compared with the HSP groups (3.148 +/- 0.291 vs. 2.795 +/- 0.122, p = 0.212), but was not significant when compared with independent samples t test. Possession of CCL3L1 copies < or = 2 or >2 was not associated with enhanced or reduced risk of HIV-1 acquisition. Gene-gene interaction studies showed enrichment of the CCR5-59029AG*CCL3L1>2 genotype in the HES group when compared with the HSP group (31.91% vs. 15.81%, p = 0.021, OR = 0.401, CI = 0.194-0.826). The increased frequency of the CCR5-59029AG*CCL3L1>2 genotype among HES individuals led us to conclude that the CCR5-59029 AG genotype and CCL3L1 gene dose appeared to have synergistic or interactive effects and are expected to be involved in the host innate resistance to HIV-1 infection.
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PMID:Association of CCR5-59029 A/G and CCL3L1 copy number polymorphism with HIV type 1 transmission/progression among HIV type 1-seropositive and repeatedly sexually exposed HIV type 1-seronegative North Indians. 1988 39

We examined the effect of CCL3L1 gene copy number on disease progression in a North American white cohort of HIV-1-infected individuals. Although CCL3L1 copy number is enriched in uninfected Caucasians, in HIV-1-infected individuals CCL3L1 copy number did not correlate either with long-term nonprogression or with CD4 cell count or viral load in chronic progressors. These findings underscore the heterogeneity of factors involved with long-term nonprogression when comparing cohorts of varying ethnic backgrounds.
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PMID:The impact of CCL3L1 copy number in an HIV-1-infected white population. 2044 35


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