Article

Meta-analysis to test the association of HIV-1 nef amino acid differences and deletions with disease progression

2M, UCD-CASL (Complex and Adaptive Systems Laboratory), University College Dublin, Belfield, Dublin 4, Ireland.
Journal of Virology (Impact Factor: 4.65). 04/2010; 84(7):3644-53. DOI: 10.1128/JVI.01959-09
Source: PubMed

ABSTRACT Previous relatively small studies have associated particular amino acid replacements and deletions in the HIV-1 nef gene with differences in the rate of HIV disease progression. We tested more rigorously whether particular nef amino acid differences and deletions are associated with HIV disease progression. Amino acid replacements and deletions in patients' consensus sequences were investigated for 153 progressor (P), 615 long-term nonprogressor (LTNP), and 2,311 unknown progressor sequences from 582 subtype B HIV-infected patients. LTNPs had more defective nefs (interrupted by frameshifts or stop codons), but on a per-patient basis there was no excess of LTNP patients with one or more defective nef sequences compared to the Ps (P = 0.47). The high frequency of amino acid replacement at residues S(8), V(10), I(11), A(15), V(85), V(133), N(157), S(163), V(168), D(174), R(178), E(182), and R(188) in LTNPs was also seen in permuted datasets, implying that these are simply rapidly evolving residues. Permutation testing revealed that residues showing the greatest excess over expectation (A(15), V(85), N(157), S(163), V(168), D(174), R(178), and R(188)) were not significant (P = 0.77). Exploratory analysis suggested a hypothetical excess of frameshifting in the regions (9)SVIG and (118)QGYF among LTNPs. The regions V(10) and (152)KVEEA of nef were commonly deleted in LTNPs. However, permutation testing indicated that none of the regions displayed significantly excessive deletion in LTNPs. In conclusion, meta-analysis of HIV-1 nef sequences provides no clear evidence of whether defective nef sequences or particular regions of the protein play a significant role in disease progression.

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Available from: Ravindra Pushker, Oct 02, 2014
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    • "Rapid progression to AIDS (within 3 years after seroconversion (Casado et al., 2010)) has been associated to virus genetics (Pushker et al., 2010; Lemey et al., 2007; Ng et al., 2014), epidemiological factors (Helleberg et al., 2013; Murphy et al., 2013), co-receptor use (Kaleebu et al., 2007), co-infection (Secor, 2012; Pawlowski et al., 2012; Alemu et al., 2013; Hernandez and Sherman, 2011), and immune activation (Liovat et al., 2012; Giorgi et al., 1999; Roberts et al., 2011). Rapid progression is associated with poorer cellular immune response (Demarest et al., 2001) and, occasionally, also to poorer HIV-specific humoral immune response (Sapsutthipas et al., 2013; Bártolo et al., 2009). "
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    • "Rapid progression to AIDS (within 3 years after seroconversion (Casado et al., 2010)) has been associated to virus genetics (Pushker et al., 2010; Lemey et al., 2007; Ng et al., 2014), epidemiological factors (Helleberg et al., 2013; Murphy et al., 2013), co-receptor use (Kaleebu et al., 2007), co-infection (Secor, 2012; Pawlowski et al., 2012; Alemu et al., 2013; Hernandez and Sherman, 2011), and immune activation (Liovat et al., 2012; Giorgi et al., 1999; Roberts et al., 2011). Rapid progression is associated with poorer cellular immune response (Demarest et al., 2001) and, occasionally, also to poorer HIV-specific humoral immune response (Sapsutthipas et al., 2013; Bártolo et al., 2009). "
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    • "It was found by full HIV-1 genome sequencing that the SBBC patients had been infected by a highly attenuated nef/LTR deleted mutant strain (Deacon et al., 1995). However, extensive analyses of viral isolates from other cohorts of EC have found that such patients are rarely infected with similar nef-deleted attenuated strains of HIV-1 (Miura et al., 2008; Pushker et al., 2010). Instead, many LTNP and EC can have fully replication competent HIV-1 (Alexander et al., 2000; Blankson et al., 2007; Lamine et al., 2007), although, more detailed studies suggest that there can be subtle decreases in function of Nef (Mwimanzi et al., 2013) or rare polymorphisms and reduced function in other genes (Alexander et al., 2000; Miura et al., 2010). "
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    ABSTRACT: Long-term non-progressors (LTNP) were identified after 10-15 years of the epidemic, and have been the subject of intense investigation ever since. In a small minority of cases, infection with nef/3'LTR deleted attenuated viral strains allowed control over viral replication. A common feature of LTNP is the readily detected proliferation of CD4 T cells in vitro, in response to p24. In some cases, the responding CD4 T cells have cytotoxic effector function and may target conserved p24 epitopes, similar to the CD8 T cells described below. LTNP may also carry much lower HIV DNA burden in key CD4 subsets, presumably resulting from lower viral replication during primary infection. Some studies, but not others, suggest that LTNP have CD4 T cells that are relatively resistant to HIV infection in vitro. One possible mechanism may involve up-regulation of the cell cycle regulator p21/waf in CD4 T cells from LTNP. Delayed progression in Caucasian LTNP is also partly associated with heterozygosity of the ∆32 CCR5 allele, probably through decreased expression of CCR5 co-receptor on CD4 T cells. However, in approximately half of Caucasian LTNP, two host genotypes, namely HLA-B57 and HLA-B27, are associated with viral control. Immunodominant CD8 T cells from these individuals target epitopes in p24 that are highly conserved, and escape mutations have significant fitness costs to the virus. Furthermore, recent studies have suggested that these CD8 T cells from LTNP, but not from HLA-B27 or HLA-B57 progressors, can cross-react with intermediate escape mutations, preventing full escape via compensatory mutations. Humoral immunity appears to play little part in LTNP subjects, since broadly neutralizing antibodies are rare, even amongst slow progressors. Recent genome wide comparisons between LTNP and progressors have confirmed the HLA-B57, HLA-B27 and delta32 CCR5 allelic associations, plus indicated a role for HLA-C/KIR interactions, but have not revealed any new genotypes so far.
    Frontiers in Immunology 04/2013; 4:95. DOI:10.3389/fimmu.2013.00095
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