Analysis of Near Full-Length Genomic Sequences of Drug-Resistant HIV-1 Spreading among Therapy-Naïve Individuals in Nagoya, Japan: Amino Acid Mutations Associated with Viral Replication Activity
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Tokai Area Central Hospital for AIDS Treatment and Research, Nagoya, Aichi 460-0001, Japan. AIDS research and human retroviruses
(Impact Factor: 2.33).
08/2008; 24(8):1121-5. DOI: 10.1089/aid.2008.0090
We analyzed a total of 12 near full-length genomes of drug-resistant HIV-1 spreading among therapy-naïve individuals in Nagoya, Japan. Genomes comprised seven protease inhibitor (PI)-resistant viruses possessing an M46I (n = 6) or L90M mutation (n = 1) and five non-nucleoside reverse transcriptase inhibitor-resistant viruses possessing a K103N mutation. All 12 viruses conserved both an H87Q mutation in the cyclophilin A-binding site of Gag p24 (capsid) and a T23N mutation in the cysteine-rich domain of Tat protein. PI-resistant viruses commonly possessed two cleavage site mutations in the p6(Pol)/protease of Pol polyprotein (F48L in p6(Pol)) and the anchor/core domains of Nef protein (L57V). These amino acid mutations represent candidates for enhancing replication activity of drug-resistant viruses and supporting expansion of such viruses in therapy-naïve individuals.
Available from: Raquel Amorim
- "However, the sequence from patient LTSP_17 presented a deletion of six amino acids within the Cterminal flexible-loop in the close proximity to the very conserved LL domain of Nef that could predict the loss of most functions attributed to this protein (Fig. 1). Furthermore, the sequence from EC_01 had a mutation at the Leucine residue within the CAWL domain , which is recognized by the PR as a cleavage site and is also involved in CD4 down modulation [Miller et al., 1997; Ibe et al., 2008]. Although the L69V mutation observed in this patient is functionally conserved , in terms of membrane-bound proteins, Leucine to Valine substitution is not a preferred mutation . "
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ABSTRACT: Progression towards AIDS can vary from 5 to 10 years from the establishment of the primary infection by HIV-1 to more than 10 years in the complete absence of antiretroviral therapy. Several factors can contribute to the outcome of HIV infection, including host genetic and viral replicating characteristics. Historically, nef-deleted viral genomes have been associated with disease progression. Therefore, the lentiviral Nef protein is regarded as a progression factor. The objective of this work was to characterize the nef gene from a group of treatment naive patients infected with HIV-1 for more than 10 years. These patients were classified as long-term non-progressors, elite controller, and slow-progressors according to clinical and laboratorial data. A premature stop codon within the nef gene leading to the expression of a truncated peptide was observed on samples from the elite controller patient. For the slow-progressor patients, several degrees of deletions at the C-terminal of Nef were observed predicting a loss of function of this protein. The vif gene was characterized for these patients and a rare mutation that predicts a miss localization of the Vif protein to the nucleus of infected cells that could prevent its function as an APOBEC neutralization factor was also observed. These data indicate the importance of the HIV accessory proteins as factors that contribute to the outcome of AIDS. J. Med. Virol. 85:563-574, 2013. © 2013 Wiley Periodicals, Inc.
Available from: Tatsuo Shioda
- "Amino acid residue 87H is located in the L4/5 and H87Q mutation reduces incorporation of cyclophilin A (CypA) into HIV-1 virions (Gatanaga et al., 2006). H87Q was also observed in protease inhibitor-resistant viruses (Gatanaga et al., 2002) as well as non-nucleoside reverse transcriptase inhibitor-resistant viruses (Ibe et al., 2008). It remains to be elucidated whether mutations in CTL escape or drug-resistant viruses and compensatory mutations in revertant viruses affect viral sensitivity to human TRIM5α. "
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ABSTRACT: Human immunodeficiency virus (HIV) has a very narrow host range. HIV type 1 (HIV-1) does not infect Old World monkeys, such as the rhesus monkey (Rh). Rh TRIM5α was identified as a factor that confers resistance, intrinsic immunity, to HIV-1 infection. Unfortunately, human TRIM5α is almost powerless to restrict HIV-1. However, human TRIM5α potently restricts N-tropic murine leukemia viruses (MLV) but not B-tropic MLV, indicating that human TRIM5α represents the restriction factor previously designated as Ref1. African green monkey TRIM5α represents another restriction factor previously designated as Lv1, which restricts both HIV-1 and simian immunodeficiency virus isolated from macaque (SIVmac) infection. TRIM5 is a member of the tripartite motif family containing RING, B-box2, and coiled-coil domains. The RING domain is frequently found in E3 ubiquitin ligase, and TRIM5α is thought to degrade viral core via ubiquitin-proteasome-dependent and -independent pathways. The alpha isoform of TRIM5 has an additional C-terminal PRYSPRY domain, which is a determinant of species-specific retrovirus restriction by TRIM5α. On the other hand, the target regions of viral capsid protein (CA) are scattered on the surface of core. A single amino acid difference in the surface-exposed loop between α-helices 6 and 7 (L6/7) of HIV type 2 (HIV-2) CA affects viral sensitivity to human TRIM5α and was also shown to be associated with viral load in West African HIV-2 patients, indicating that human TRIM5α is a critical modulator of HIV-2 replication in vivo. Interestingly, L6/7 of CA corresponds to the MLV determinant of sensitivity to mouse factor Fv1, which potently restricts N-tropic MLV. In addition, human genetic polymorphisms also affect antiviral activity of human TRIM5α. Recently, human TRIM5α was shown to activate signaling pathways that lead to activation of NF-κB and AP-1 by interacting with TAK1 complex. TRIM5α is thus involved in control of viral infection in multiple ways.
Available from: Andreas Leiherer
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ABSTRACT: The HIV-1 transframe protein p6 known to modulate HIV-1 protease activation has been suggested to interact with the viral pathogenicity factor Nef. However, a potential interaction site in p6 has not been mapped so far. To evaluate effects of p6 modification on viral replication in light of Nef function, clustered substitutions were introduced into the central p6 region of the infectious provirus NL4-3 and virus growth and composition of the various mutants was analyzed in different cell cultures in the presence or absence of Nef. Whereas clustered p6 substitutions did neither affect particle incorporation of Nef, nor precursor maturation or viral infectivity, a simultaneous substitution of 40 of the total 56 p6 residues significantly diminished viral infectivity and replication in a Nef-independent manner. Furthermore, this extended modification was not capable of rescuing the negative effects of a transdominant Nef mutant on particle production suggesting that the proposed target for Nef interaction in Gag-Pol is located outside the modified p6 region. In sum these data strongly argue against a functional connection of the central p6 region and Nef during viral life cycle.
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