Impact of host genetics on HIV disease progression and treatment

Nolan, David; Gaudieri, Silvana; John, Mina; Mallal, S.

doi:10.1097/00002030-200406180-00001

Cited by 23 publications

(14 citation statements)

References 96 publications

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“…4 As expected, HLA-B*5701 (P ¼ 0.002), -B*2705 (P ¼ 0.07), -B Bw4 (P ¼ 0.02) and CCR5D32 (P ¼ 0.04) were strongly associated with a significantly lower viral load set point, 1,2,31 although the effects of HLA-B Bw4 were abrogated in multivariate analysis adjusted for the Bw4-associated alleles HLA-B*5701 and -B*2705. No significant associations between any KIR gene and viral load set point were detected (all had a P40.2).…”

Section: Hla and Kir Genotype Have Different Effects On Initial %Cd4supporting

confidence: 65%

“…1,2 For example, the ability to mount an effective and durable cytotoxic T-lymphocyte response to HIV has been shown to influence pretreatment viral load, 3,4 which in turn predicts CD4 þ decline and progression to AIDS. 3,[5][6][7] In this context, associations between viral load set point and particular HLA class I alleles and MHC haplotypes have been identified, [8][9][10][11] with evidence that HLA-restricted immune responses represent a major selective force for viral adaptation at both the individual and population level.…”

Section: Introductionmentioning

confidence: 99%

“…4 However, other genetic factors such as the NK cell receptors, Killer Immunoglobulin-like Receptor (KIR) genes, which directly interact with HLA could also affect the susceptibility of CD4 þ T-cells to undergo cell lysis independent of the viral burden, and may also play a role in determining the development of individual AIDSdefining illnesses by specifically shaping the immunological response to opportunistic pathogens. 1,2 The KIR genes on chromosome 19p13.4, like the HLA genes on chromosome 6p21.3, are recognition molecules critical for host immune responses and are encoded within a highly polymorphic region of the human genome. The KIR gene complex demonstrates strong interlocus linkage disequilibrium (LD), producing a number of relatively common KIR genotypes [12][13][14][15] that can be resolved into two broad haplotypes (denoted 'A' and 'B') consisting of a centromeric and a telomeric region separated by framework loci that are common to both haplotypes (see Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

et al. 2005

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Section: Hla and Kir Genotype Have Different Effects On Initial %Cd4supporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

et al. 2005

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“…Given the HLA-B*5701 phenotype frequency of 8.5% in our cohort, we can predict that Ϸ14 individuals would need to be screened for HLA-B*5701 to prevent one case of abacavir hypersensitivity. Taken together, these data indicate that prospective genetic testing for abacavir hypersensitivity is likely to be highly predictive, and, at least in populations of European descent, in which the HLA-B*5701 allele is relatively common, costeffective (35).…”

Section: Discussionmentioning

confidence: 78%

Predisposition to abacavir hypersensitivity conferred byHLA-B**5701*and a haplotypicHsp70-Homvariant

Martin

Nolan

Gaudieri

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Susceptibility to a clinically significant drug hypersensitivity syndrome associated with abacavir use seems to have a strong genetic component. We have previously shown that the presence of HLA-B*5701 strongly predicts abacavir hypersensitivity and have identified a potential susceptibility locus within a 300-kb region between the MEGT1 and C4A6 loci in the central MHC. We now report the results of fine recombinant genetic mapping in an expanded patient population of 248 consecutive, fully ascertained, abacavir-exposed individuals in the Western Australian HIV Cohort Study, in which 18 cases of definite abacavir hypersensitivity (7.3%) and 230 tolerant controls were identified. Haplotype mapping within patients with allelic markers of the 57.1 ancestral haplotype suggests a susceptibility locus within the 14-kb Hsp70 gene cluster. HLA-B*5701 was present in 94.4% of hypersensitive cases compared with 1.7% of controls (odds ratio, 960; P < 0.00001). A haplotypic nonsynonymous polymorphism of Hsp70-Hom (HspA1L, resulting from the substitution of residue M493T in the peptide-binding subunit) was found in combination with HLA-B*5701 in 94.4% of hypersensitive cases and 0.4% of controls (odds ratio, 3,893; P < 0.00001). Individuals with abacavir hypersensitivity demonstrated increased monocyte tumor necrosis factor expression in response to ex vivo abacavir stimulation, which was abrogated with CD8 ؉ T cell depletion. These data indicate that the concurrence of HLA-B*5701 and Hsp70-Hom M493T alleles is necessary for the development of abacavir hypersensitivity, which is likely to be mediated by an HLA-B*5701-restricted immune response to abacavir.ancestral haplotype ͉ microsatellite ͉ human leukocyte antigen ͉ single-nucleotide polymorphism

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“…17). These HLA factors may further benefit seronegative individuals who are at high risk of acquiring infection because viral load in plasma or genital secretions of a seropositive partner is highly predictive of HIV-1 transmission potential (18, 19).…”

mentioning

confidence: 99%

Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples

Tang¹,

Shao²,

Yoo

et al. 2008

The Journal of Immunology

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Differences in immune control of HIV-1 infection are often attributable to the highly variable HLA class I molecules that present viral epitopes to CTL. In our immunogenetic analyses of 429 HIV-1 discordant Zambian couples (infected index partners paired with cohabiting seronegative partners), several HLA class I variants in index partners were associated with contrasting rates and incidence of HIV-1 transmission within a 12-year study period. In particular, A*3601 on the A*36-Cw*04-B*53 haplotype was the most unfavorable marker of HIV-1 transmission by index partners, while Cw*1801 (primarily on the A*30-Cw*18-B*57 haplotype) was the most favorable, irrespective of the direction of transmission (male to female or female to male) and other commonly recognized cofactors of infection, including age and GUI. The same HLA markers were further associated with contrasting viral load levels in index partners, but they had no clear impact on HIV-1 acquisition by the seronegative partners. Thus, HLA class I gene products not only mediate HIV-1 pathogenesis and evolution but also influence heterosexual HIV-1 transmission.

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Impact of host genetics on HIV disease progression and treatment

Cited by 23 publications

References 96 publications

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

Predisposition to abacavir hypersensitivity conferred byHLA-B**5701*and a haplotypicHsp70-Homvariant

Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples

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Impact of host genetics on HIV disease progression and treatment

Cited by 23 publications

References 96 publications

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression

Predisposition to abacavir hypersensitivity conferred byHLA-B*5701and a haplotypicHsp70-Homvariant

Human Leukocyte Antigen Class I Genotypes in Relation to Heterosexual HIV Type 1 Transmission within Discordant Couples

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Predisposition to abacavir hypersensitivity conferred byHLA-B**5701*and a haplotypicHsp70-Homvariant