Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics

ABSTRACT India is experiencing a rapid spread of human immunodeficiency virus type 1 (HIV-1), primarily through heterosexual transmission of subtype C viruses. To delineate the molecular features of HIV-1 circulating in India, we sequenced the V3-V4 region of viralenv from 21 individuals attending an HIV clinic in Calcutta, the most populous city in the eastern part of the country, and analyzed these and the other Indian sequences in the HIV database. Twenty individuals were infected with viruses having a subtype Cenv, and one had viruses with a subtype Aenv. Analyses of 192 subtype C sequences that included one sequence for each subject from this study and from the HIV database revealed that almost all sequences from India, along with a small number from other countries, form a phylogenetically distinct lineage within subtype C, which we designate CIN. Overall, CIN lineage sequences were more closely related to each other (level of diversity, 10.2%) than to subtype C sequences from Botswana, Burundi, South Africa, Tanzania, and Zimbabwe (range, 15.3 to 20.7%). Of the three positions identified as signature amino acid substitution sites for CIN sequences (K340E, K350A, and G429E), 56% of the CIN sequences contained all three amino acids while 87% of the sequences contained at least two of these substitutions. Among the non-CINsequences, all three amino acids were present in 2%, while 22% contained two or more of these amino acids. These results suggest that much of the current Indian epidemic is descended from a single introduction into the country. Identification of conserved signature amino acid positions could assist epidemiologic tracking and has implications for the development of a vaccine against subtype C HIV-1 in India.

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Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04215-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 960-971 ◽

Cited By ~ 34

Author(s):

Adriaan E. Basson ◽

Soo-Yon Rhee ◽

Chris M. Parry ◽

Ziad El-Khatib ◽

Salome Charalambous ◽

...

Keyword(s):

Amino Acid ◽

Reverse Transcriptase ◽

Resistance Testing ◽

Amino Acid Substitutions ◽

Subtype C ◽

Nnrti Resistance ◽

High Level ◽

Hiv 1 ◽

Phenotypic Susceptibility ◽

Level Resistance

ABSTRACTThe objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in anin vitrosingle-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.

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Detection of the protease codon 35 amino acid insertion in sequences from treatment-naïve HIV-1 subtype C infected individuals in the Central Region of Portugal

Journal of Clinical Virology ◽

10.1016/j.jcv.2009.06.019 ◽

2009 ◽

Vol 46 (2) ◽

pp. 169-172 ◽

Cited By ~ 5

Author(s):

João Pereira-Vaz ◽

Vitor Duque ◽

Luís Trindade ◽

José Saraiva-da-Cunha ◽

António Meliço-Silvestre

Keyword(s):

Amino Acid ◽

Central Region ◽

Subtype C ◽

Amino Acid Insertion ◽

Treatment Naïve ◽

Hiv 1

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Unusual five amino acid insert within subtype C HIV-1 envelope contributes to dual-tropism (X4R5)

AIDS ◽

10.1097/qad.0b013e328331f717 ◽

2010 ◽

Vol 24 (7) ◽

pp. 1063-1064 ◽

Cited By ~ 3

Author(s):

Elizabeth Johnston White ◽

Bryan McColgan ◽

Seble Kassaye ◽

Lynn Zijenah ◽

David Katzenstein

Keyword(s):

Amino Acid ◽

Subtype C ◽

Hiv 1

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The Evolving Profile of the Signature Amino Acid Residues in HIV-1 Subtype C Tat

AIDS Research and Human Retroviruses ◽

10.1089/aid.2015.0208 ◽

2016 ◽

Vol 32 (5) ◽

pp. 503-514 ◽

Cited By ~ 1

Author(s):

Shambhu Prasad G. Aralaguppe ◽

Shilpee Sharma ◽

Malini Menon ◽

Vinayaka R. Prasad ◽

Shanmugam Saravanan ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Residues ◽

Subtype C ◽

Hiv 1

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Selected amino acid changes in HIV-1 subtype-C gp41 are associated with specific gp120V3 signatures in the regulation of co-receptor usage

Virus Research ◽

10.1016/j.virusres.2012.06.019 ◽

2012 ◽

Vol 168 (1-2) ◽

pp. 73-83 ◽

Cited By ~ 11

Author(s):

Salvatore Dimonte ◽

Muhammed Babakir-Mina ◽

Fabio Mercurio ◽

Domenico Di Pinto ◽

Francesca Ceccherini-Silberstein ◽

...

Keyword(s):

Amino Acid ◽

Subtype C ◽

Receptor Usage ◽

Hiv 1

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HLA Class I-Driven Evolution of Human Immunodeficiency Virus Type 1 Subtype C Proteome: Immune Escape and Viral Load

Journal of Virology ◽

10.1128/jvi.02455-07 ◽

2008 ◽

Vol 82 (13) ◽

pp. 6434-6446 ◽

Cited By ~ 108

Author(s):

Christine M. Rousseau ◽

Marcus G. Daniels ◽

Jonathan M. Carlson ◽

Carl Kadie ◽

Hayley Crawford ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Amino Acid ◽

Human Immunodeficiency Virus Type ◽

Viral Evolution ◽

Subtype C ◽

Hla Alleles ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) mutations that confer escape from cytotoxic T-lymphocyte (CTL) recognition can sometimes result in lower viral fitness. These mutations can then revert upon transmission to a new host in the absence of CTL-mediated immune selection pressure restricted by the HLA alleles of the prior host. To identify these potentially critical recognition points on the virus, we assessed HLA-driven viral evolution using three phylogenetic correction methods across full HIV-1 subtype C proteomes from a cohort of 261 South Africans and identified amino acids conferring either susceptibility or resistance to CTLs. A total of 558 CTL-susceptible and -resistant HLA-amino acid associations were identified and organized into 310 immunological sets (groups of individual associations related to a single HLA/epitope combination). Mutations away from seven susceptible residues, including four in Gag, were associated with lower plasma viral-RNA loads (q < 0.2 [where q is the expected false-discovery rate]) in individuals with the corresponding HLA alleles. The ratio of susceptible to resistant residues among those without the corresponding HLA alleles varied in the order Vpr > Gag > Rev > Pol > Nef > Vif > Tat > Env > Vpu (Fisher's exact test; P ≤ 0.0009 for each comparison), suggesting the same ranking of fitness costs by genes associated with CTL escape. Significantly more HLA-B (χ2; P = 3.59 × 10−5) and HLA-C (χ2; P = 4.71 × 10−6) alleles were associated with amino acid changes than HLA-A, highlighting their importance in driving viral evolution. In conclusion, specific HIV-1 residues (enriched in Vpr, Gag, and Rev) and HLA alleles (particularly B and C) confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.

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