The degree of HIV-1 amino acid variability is strictly related to different disease progression rates

Abstract Background We previously observed that individuals infected with HIV-1 CRF07_BC showed slower disease progression than those infected with HIV-1 subtype B or CRF01_AE. CRF07_BC viruses carry two unique mutations in the p6 Gag protein: insertion of PTAPPE sequences downstream of the original Tsg101 binding domain, and deletion of a seven-amino-acid sequence ( 30 PIDKELY 36 ) that partially overlaps with the Alix binding domain. To further define the role of these mutations in virus release and replication, we introduced them into the HIV-1 proviral clone pNL4-3 for functional characterization. Results We found that the seven-amino-acid deletion, but not the PTAPPE insertion, significantly decreased virus release, Gag processing, and virus infectivity. The seven-amino-acid deletion also resulted in a virus replication defect in both T-cell lines and peripheral blood mononuclear cells. We found that these defects were caused by the seven-amino-acid deletion in p6 Gag , especially deletion of Tyr-36 of p6 Gag , not the deletion of the overlapping p6* sequence in the HIV-1 GagPol protein. The p6 Gag deletion mutant was resistant to a dominant-negative Alix fragment, suggesting a loss of binding between p6 Gag and Alix. Conclusions Our results indicate that the patient-derived seven-amino-acid deletion in p6 Gag of HIV-1 CRF07_BC virus affects virus release, infectivity and replication capacity by disrupting the interaction between HIV-1 p6 Gag and host protein Alix. These results may explain the slower disease progression observed in the subjects infected with HIV-1 CRF07_BC bearing this unique mutation.

Download Full-text

Meta-Analysis To Test the Association of HIV-1 nef Amino Acid Differences and Deletions with Disease Progression

Journal of Virology ◽

10.1128/jvi.01959-09 ◽

2010 ◽

Vol 84 (7) ◽

pp. 3644-3653 ◽

Cited By ~ 13

Author(s):

Ravindra Pushker ◽

Jean-Marc Jacqué ◽

Denis C. Shields

Keyword(s):

Amino Acid ◽

Disease Progression ◽

Meta Analysis ◽

Amino Acid Replacement ◽

Hiv Disease ◽

Permutation Testing ◽

Consensus Sequences ◽

Subtype B ◽

Hiv 1

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 S8, V10, I11, A15, V85, V133, N157, S163, V168, D174, R178, E182, and R188 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 (A15, V85, N157, S163, V168, D174, R178, and R188) were not significant (P = 0.77). Exploratory analysis suggested a hypothetical excess of frameshifting in the regions 9SVIG and 118QGYF among LTNPs. The regions V10 and 152KVEEA 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.

Download Full-text

Patterns of Amino Acid Variability in NSI-like and SI-like V3 Sequences and a Linked Change in the CD4-Binding Domain of the HIV-1 Env Protein

Virology ◽

10.1006/viro.1997.8821 ◽

1997 ◽

Vol 239 (1) ◽

pp. 108-118 ◽

Cited By ~ 55

Author(s):

Lynn Milich ◽

Barry H. Margolin ◽

Ronald Swanstrom

Keyword(s):

Amino Acid ◽

Binding Domain ◽

Amino Acid Variability ◽

Env Protein ◽

Hiv 1

Download Full-text

HLA Footprints on Human Immunodeficiency Virus Type 1 Are Associated with Interclade Polymorphisms and Intraclade Phylogenetic Clustering

Journal of Virology ◽

10.1128/jvi.02017-08 ◽

2009 ◽

Vol 83 (9) ◽

pp. 4605-4615 ◽

Cited By ~ 36

Author(s):

Philippa C. Matthews ◽

Alasdair J. Leslie ◽

Aris Katzourakis ◽

Hayley Crawford ◽

Rebecca Payne ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Viral Evolution ◽

Strong Association ◽

Phylogenetic Clustering ◽

Amino Acid Variability ◽

Immunodeficiency Virus ◽

The Impact ◽

Hiv 1

ABSTRACT The selection of escape mutations has a major impact on immune control of infections with viruses such as human immunodeficiency virus (HIV). Viral evasion of CD8+ T-cell responses leaves predictable combinations of escape mutations, termed HLA “footprints.” The most clearly defined footprints are those associated with HLA alleles that are linked with successful control of HIV, such as HLA-B*57. Here we investigated the extent to which HLA footprint sites in HIV type 1 (HIV-1) are associated with viral evolution among and within clades. First, we examined the extent to which amino acid differences between HIV-1 clades share identity with sites of HLA-mediated selection pressure and observed a strong association, in particular with respect to sites of HLA-B selection (P < 10−6). Similarly, the sites of amino acid variability within a clade were found to overlap with sites of HLA-selected mutation. Second, we studied the impact of HLA selection on interclade phylogeny. Removing the sites of amino acid variability did not significantly affect clade-specific clustering, reflecting the central role of founder effects in establishing distinct clades. However, HLA footprints may underpin founder strains, and we show that amino acid substitutions between clades alter phylogeny, underlining a potentially substantial role for HLA in driving ongoing viral evolution. Finally, we investigated the impact of HLA selection on within-clade phylogeny and demonstrate that even a single HLA allele footprint can result in significant phylogenetic clustering of sequences. In conclusion, these data highlight the fact that HLA can be a strong selection force for both intra- and interclade HIV evolution at a population level.

Download Full-text