Genetic Analysis and Natural Polymorphisms in HIV-1 gp41 Isolates from Maputo City, Mozambique

Abstract

Enfuvirtide was the first fusion inhibitor approved by the Food and Drug Administration (FDA) in 2003 for HIV-1 infection in treatment-experienced patient. It is the first approved antiviral agent to attack the HIV life cycle in its early stages. For HIV fusion to occur, the HR1 and HR2 domains in the gp41 region need to interact. Enfuvirtide is a synthetic peptide that corresponds to 36 amino acids of the HR2, which competitively binds to HR1 inhibiting the interaction with the HR2 domain thus preventing fusogenic conformation and inhibiting viral entry into host cells. Resistance to enfuvirtide is conferred by mutations occurring in the HR1 region involving residues 36-45. Mozambique, a sub-Saharan country, with an HIV prevalence of 11.5%, provides first line and second line antiretroviral therapy (ART)-based treatment. In poor resource settings such as Mozambique the lack of adequate infrastructures, the high costs of viral load tests, and the availability of salvage treatment have hindered the intended objective of monitoring HIV treatment, suggesting an important concern regarding the development of drug resistance. The general aim of this study was to evaluate naturally occurring polymorphisms and resistance-associated mutations in the gp41 region of HIV-1 isolates from Mozambique. The study included 78 patients naive to ARV treatment and 28 patients failing first line regimen recruited from Centro de Saú de Alto-Maé situated in Maputo. The gp41 gene from 103 patients was sequenced and resistance-associated mutations for enfuvirtide were screened. Subtype analysis revealed that 96% of the sequences were classified as subtype C, 2% as subtype G, 1% as subtype A1, and the other 1% as a mosaic form composed of A1/C. No enfuvirtide resistance-associated mutations in HR1 of gp41 were detected. The major polymorphisms in the HR1 were N42S, L54M, A67T, and V72I. This study suggests that this new class of antiviral drug may be effective as a salvage therapy in patients failing first line regimens in Mozambique. However, further phenotypic studies are required to determine the clinical relevance of the polymorphisms detected in this study. 1 Mozambique, a sub-Saharan country, faces serious HIV epidemics with a national prevalence of 11.5% of adults aged 15-49 years; the overall prevalence rate is 17.8% in the southern region, 12.5% in the central region, and 5.6% in the northern region.2 Thus, according to the Ministry of Health in 2010 the number of people receiving antiretroviral treatment (ART) was approximately 211,000 adults and 16,800 children and the ART coverage for people in need of treatment was 40% for adults and 26% for children. 3As recommended by the WHO, the first line ART regimen in Mozambique consists of two nucleoside reverse transcriptase inhibitors (NRTIs) and one nonnucleoside reverse transcriptase inhibitor (NNRTI) and the second line ART regimen consists of a boosted protease inhibitor (PIs) and two NRTIs for patients failing the first line regimen. However, due to the rapid expansion...

Unique genotypic features of HIV-1 C gp41 membrane proximal external region variants during pregnancy relate to mother-to-child transmission via breastfeeding

“…While MPER regions displayed a trend toward increased maximum biodiversity, the striking biochemical characteristics of viral populations associated with MTCT by breastfeeding were restricted to MPER. Although HR2 and MSD segments that flank MPER were diverse, patterns of diversity were unrelated to transmission outcomes, perhaps reflecting HR2 interactions with HR1 or a role for MSD in anchoring gp41 in membranes [ 97 – 102 ]. Overall, deep sequencing coupled with an efficient bioinformatics pipeline provided unprecedented coverage of HIV-1 gp41 MPER quasispecies combined with sensitive detection of low frequency variants that can only be captured by high coverage of input viral copies.…”

Unique Genotypic Features of HIV-1 C Gp41 Membrane Proximal External Region Variants during Pregnancy Relate to Mother-to-child Transmission via Breastfeeding

“…While MPER regions displayed a trend toward increased maximum biodiversity, the striking biochemical characteristics of viral populations associated with MTCT by breastfeeding were restricted to MPER. Although HR2 and MSD segments that flank MPER were diverse, patterns of diversity were unrelated to transmission outcomes, perhaps reflecting HR2 interactions with HR1 or a role for MSD in anchoring gp41 in membranes (64,87–90). Overall, deep sequencing coupled with an efficient bioinformatics pipeline provided unprecedented coverage of HIV-1 gp41 MPER quasispecies combined with sensitive detection of low frequency variants that can only be captured by high coverage of input viral copies.…”

Intradermal HIV-1 DNA Immunization Using Needle-Free Zetajet Injection Followed by HIV-Modified Vaccinia Virus Ankara Vaccination Is Safe and Immunogenic in Mozambican Young Adults: A Phase I Randomized Controlled Trial

“…Nevertheless, the comparison between proportions and magnitudes of IFN-c ELISpot responses after the first and second HIV-MVA boost was not significantly affected. HIV infections in Mozambique are predominantly subtype C [41][42][43][44] and we limited binding antibody assessment and NAb testing using the TZM-bl/pseudovirus assay to detection of subtype C-and subtype B-specific antibodies despite HIV-MVA being CRF01_AE CM235 specific. The use of a broader panel of antigens/pseudoviruses that include CRF01_AE and other subtypes would be useful to probe antibody breadth in the future.…”