WJA  Vol.4 No.2 , June 2014
Antiretroviral-Drug Resistant Mutations and Genetic Diversity in HIV-1 Infected Individuals in Nigeria
Abstract: Introduction: Despite the success derived from antiretroviral therapy, drug resistance (DR) mutations are known to develop and are major impediments to treatment of HIV patients. Therefore, periodic assessment of HIVDR is needed to ensure continuous HAART efficacy. This study assessed the magnitude of drug resistance as well as HIV genetic variability in drug-naive and treated patients in Nigeria. Methodology: Genotypic analysis was performed by sequencing plasma specimens from 40 individuals in a cross sectional study involving 202 HIV infected patients from all the six geopolitical zones of Nigeria. Sequences were analyzed for presence of HIVDR mutation using the algorithm in Stanford HIVDR database and confirmed by IAS-USA 2009 mutation list. Phylogenetic and recombination analyses were done using PAUP V4.0 and REGA V2.0 respectively. Results: Major DR mutations were detected in the reverse transcriptase (RT) gene of 5 (33%) drug experienced and 2 (8%) na?ve patients. Most common mutations were M184V and K103N with no protease (PR) mutations detected. Thymidine analogue mutations (TAMs) and a complex multi resistance mutation Q151M were detected in 3 samples. Polymorphic substitutions were observed in both PR and RT gene. Phylogenetic analysis revealed Group M isolates of G (20), J (1), circulating recombinant forms: CRF02_AG (14), CRF-18-cpx (1), CRF06_cpx (3) and a unique AD recombinant (1). Conclusion: Our findings corroborate previous studies on circulating DR viruses in Nigeria while genetic diversity is on the increase. In view of ART scale-up, monitoring the resistance pattern and genetic diversity will aid in appropriate prevention strategies.
Cite this paper: Negedu-Momoh, O. , Olonitola, O. , Odama, L. , Inabo, H. , Mbah, H. , Kasembeli, A. , Inzaule, S. , Oladele, E. , Badru, T. and Agwale, S. (2014) Antiretroviral-Drug Resistant Mutations and Genetic Diversity in HIV-1 Infected Individuals in Nigeria. World Journal of AIDS, 4, 187-197. doi: 10.4236/wja.2014.42024.

[1]   Takehisa, J. and Miura, T. (2010) The Origin and Evolution of HIV. Journal of Japanese Clinical Medicine, 68, 410-414

[2]   Robertson, D.L., Anderson, J.P., Bradac, J.A., et al. (2000) HIV-1 Nomenclature Proposal. Science, 288, 55-56.

[3]   Osmanov, S., Pattou, C., Walker, N., Schwardlander, B. and Esparza, J. (2002) Estimated Global Distribution and Regional Spread of HIV-1 Genetic Subtypes in the Year 2000. Journal of Acquired Immune Deficiency Syndromes, 29, 184-190.

[4]   Egger, M., Hirschel, B., Francioli, P., Sudre, P., Wirz, M., Flepp, M., Rickenbach, M., Malinverni, R., Vernazza, P. and Battegay, M. (1997) Impact of New Antiretroviral Combination Therapies in HIV Infected Patients in Switzerland: Prospective Multicentre Study.. BMJ, 315, 1194.

[5]   Shafer, R.W. (2002) Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance. Clinical Microbiology Reviews, 15, 247-277.

[6]   Yerly, S., Kaiser, L., Race, E., Bru, J.P., Clavel, F. and Perrin, L. (1999) Transmission of Antiretroviral-Drug-Resistant HIV-1 Variants. Lancet, 354, 729-733.

[7]   Wainberg, M.A. (2004) HIV-1 Subtype Distribution and the Problem of Drug Resistance. AIDS, 18, S63-S68.

[8]   Kantor, R. and Katzenstein, D. (2004) Drug Resistance in Non-Subtype B HIV-1. Journal of Clinical Virology, 29, 152-159.

[9]   Wainberg, M.A. and Brenner, B.G. (2010) Role of HIV Subtype Diversity in the Development of Resistance to Antiviral Drugs. Viruses, 2, 2493-2508.

[10]   Population Reference Bureau (2013) World Population Data Sheet.

[11]   Federal Ministry of Health, Nigeria (2010) Technical Report on HIV Sentinel Survey among Pregnant Women Attending Antenatal Clinics in Nigeria.

[12]   Olaleye, O.D., Bernstein, L., Ekweozor, C.C., Sheng, Z., Omilabu, S.A., Li, X.Y., Sullivan-Halley, J and Rasheed, S. (1993) Prevalence of Human Immunodeficiency Virus Types 1 and 2 Infections in Nigeria. The Journal of Infectious Diseases, 167, 710-714.

[13]   Federal Ministry of Health, Nigeria (2010) National Guidelines for HIV/AIDS Treatment and Care in Adolescence and adults, 60-62.

[14]   Howard, T.M. and Rasheed, S. (1996) Genomic Structure and Nucleotide Sequence Analysis of a New HIV Type 1 Subtype A Strain from Nigeria. AIDS Research and Human Retroviruses, 12, 1413-1425.

[15]   Agwale, S.M., Robbins, K.E., Odama, L., et al. (2001) Development of an env gp41-Based Heteroduplex Mobility Assay for Rapid Human Immunodeficiency Virus Type 1 Subtyping. Journal of Clinical Microbiology, 39, 2110-2114.

[16]   Agwale, S.M., Zeh, C., Robbins, K.E., Odama, L., Saekhou, A., Edubio, A., Njoku, M., Sani-Gwarzo, N., Gboun, M.S., Gao, F., Reitz, M., Hone, D., Pieniazek, D., Wambebe, C. and Kalish, M.L. (2002) Molecular Surveillance of HIV-1 Field Strains in Nigeria in Preparation for Vaccine Trials. Vaccine, 20, 2131-2139.

[17]   Ojesina, A.I., Sankale, J.L., Odaibo, G., Langevin, S., Meloni, S.T., Sarr, A.D., Olaleye, D. and Kanki, P.J. (2006) Subtype-Specific Patterns in HIV Type 1 Reverse Transcriptase and Protease in Oyo State, Nigeria: Implications for Drug Resistance and Host Response. AIDS Research and Human Retroviruses, 22, 770-779.

[18]   McNulty, A., Jennings, C., Bennett, D., Fitzgibbon, J., Bremer, J.W., Ussery, M., Kalish, M.L., Heneine, W. and García-Lerma, J.G. (2007) Evaluation of Dried Blood Spots for Human Immunodeficiency Virus Type 1 Drug Resistance Testing. Journal of Clinical Microbiology, 45, 517-521.

[19]   Yang, C., McNulty, A., Diallo, K., Zhang, J., Titanji, B., Kassim, S., Wadonda-Kabondo, N., Aberle-Grasse, J., Kibuka, T., Ndumbe, P.M., Vedapuri, S., Zhou, Z.Y., Chilima, B. and Nkengasong, J.N. (2010) Development and Application of a Broadly Sensitive Dried-Blood-Spot-Based Genotyping Assay for Global Surveillance of HIV-1 Drug Resistance. Journal of Clinical Microbiology, 48, 3158-3164.

[20]   Johnson, V.A., Brun-Vézinet, F., Clotet, B., Günthard, H.F., Kuritzkes, D.R., Pillay, D., Schapiro, J.M. and Richman, D.D. (2010) Update of the Drug Resistance Mutations in HIV-1: December 2010. Topics in HIV Medicine, 18, 156-163.

[21]   Rambaut, A. (2002) Sequence Alignment Editor (Version 2.0). Oxford University.

[22]   Swofford, D.L., Begle, D.P. and Dc, W. (2000) Phylogenetic Analysis Using Parsimony, Version 4.0b4. Sinauer, Sunderland.

[23]   Mouroux, M., Descamps, D., Izopet, J., Yvon, A., Delaugerre, C., Matheron, S., Coutellier, A., Valantin, M.A., Bonmarchand, M., Agut, H., Massip, P., Costagliola, D., Katlama, C., Brun-Vezinet, F. and Calvez, V. (2001) Low-Rate Emergence of Thymidine Analogue Mutations and Multi-Drug Resistance Mutations in the HIV-1 Reverse Transcriptase Gene in Therapy-Naive Patients Receiving Stavudine Plus Lamivudine Combination Therapy. Antiviral Therapy, 6, 179-183.

[24]   Iversen, A.K.N., Shafer, R.W., Wehrly, K., Winters, M.A., Mullins, J.I., Chesebro, B. and Merigan, T.C. (1996) Multidrug-Resistant Human Immunodeficiency Virus Type 1 Strains Resulting from Combination Antiretroviral Therapy. Journal of Virology, 70, 1086-1090.

[25]   Miller, V. and Larder, B.A. (2001) Mutational Patterns in the HIV Genome and Cross-Resistance Following Nucleoside and Nucleotide Analogue Drug Exposure. Antiviral Therapy, 6, 25-44.

[26]   Deeks, S.G. (2001) Nonnucleoside Reverse Transcriptase Inhibitor Resistance. JAIDS Journal of Acquired Immune Deficiency Syndromes, 26, S25-S33.

[27]   D’Aquila, R.T., Schapiro, J.M., Brun-Vezinet, F., et al. (2002) Drug Resistance Mutations in HIV-1. Topics in HIV Medicine, 10, 21-25. (Special Contribution)

[28]   Petropoulos, C.J., Parkin, N.T., Limoli, K.L., Lie, Y.S., Wrin, T., Huang, W., Tian, H., Smith, D., Winslow, G.A., Capon, D.J. and Whitcomb, J.M. (2000) A Novel Phenotypic Drug Susceptibility Assay for Human Immunodeficiency Virus Type 1. Antimicrobial Agents and Chemotherapy, 44, 920-928.

[29]   Huang, W., Gamarnik, A., Limoli, K., Petropoulos, C.J. and Whitcomb, J.M. (2003) Amino Acid Substitutions at Position 190 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Increase Susceptibility to Delavirdine and Impair Virus Replication. Journal of Virology, 77, 1512-1523.

[30]   Agwale, S.M., Zeh, C., Paxinos, E., Odama, L., Pienazek, D., Wambebe, C., Kalish, M.L. and Ziermann, R. (2006) Genotypic and Phenotypic Analyses of Human Immunodeficiency Virus Type 1 in Antiretroviral Drug-Naive Nigerian Patients. AIDS Research and Human Retroviruses, 22, 22-26.

[31]   Paxinos, E., Womac, C., Galovich, J., et al. (2004) Emergence of Drug Resistant Human Immunodeficiency Virus during the Era of Massive Antiretroviral therapy in Nigeria. Aids Vaccines and Related Topics, Research Signpost, Trivandrum, 121-123.

[32]   Cane, P., Chrystie, I., Dunn, D., et al. (2005) Time Trends in Primary Resistance to HIV Drugs in the United Kingdom: Multicentre Observational Study. British Medical Journal, 331, 1368.

[33]   Boucher, C.A., O’Sullivan, E., Mulder, J.W., Ramautarsing, C., Kellam, P., Darby, G., Lange, J.M., Goudsmit, J. and Larder, B.A. (1992) Ordered Appearance of Zidovudine Resistance Mutations during Treatment of 18 Human Immunodeficiency Virus-Positive Subjects. Journal of Infectious Diseases, 165, 105-110.

[34]   Lindstrpom, A., Ohlis, A., Huigen, M., Nijhuis, M., Berglund, T., Bratt, G., Sandstrom, E. and Albert, J. (2006) HIV-1 Transmission Cluster with M41L “Singleton” Mutation and Decreased Transmission of Resistance in Newly Diagnosed Swedish Homosexual Men. Antiviral Therapy, 11, 1031-1039.

[35]   Coffin, J.M. (1995) HIV Population Dynamics in Vivo: Implications for Genetic Variation, Pathogenesis, and Therapy. Science, 267, 483-489.

[36]   Adje-Toure, C., Bile, C.E., Borget, M.Y., Hertog, K., Maurice, C., Nolan, M.L. and Nkengasong, J.N. (2003) Polymorphism in Protease and Reverse Transcriptase and Phenotypic Drug Resistance of HIV-1 Recombinant CRF02_AG Isolates from Patients with No Prior Use of Antiretroviral Drugs in Abidjan, Cote d’Ivoire. JAIDS Journal of Acquired Immune Deficiency Syndromes, 1, 111-113.

[37]   Vergne, L., Diagbouga, S., Kouanfack, C., Aghokeng, A., Butel, C., Laurent, C., Noumssi, N., Tardy, M., Sawadogo, A., Drabo, J., Hien, H., Zekeng, L., Delaporte, E. and Peeters, M. (2006) HIV-1 Drug-Resistance Mutations among Newly Diagnosed Patients before Scaling-Up Programmes in Burkina Faso and Cameroon. Antiviral Therapy, 11, 575-579.

[38]   Tanuri, A., Caridea, E., Dantas, M.C., et al. (2002) Prevalence of Mutations Related to HIV-1 Antiretroviral Resistance in Brazilian Patients Failing HAART. Journal of Clinical Virology, 25, 39-46.

[39]   Wainberg, M.A. and Friedland, G. (1998) Public Health Implications of Antiretroviral Therapy and HIV Drug Resistance. JAMA, 279, 1977-1983.

[40]   Hirsch, M.S., Brun-Vezinet, F., Clotet, B., Conway, B., Kuritzkes, D.R., D’Aquila, R.T., Demeter, L.M., Hammer, S.M., Johnson, V.A., Loveday, C., Mellors, J.W., Jacobsen, D.M. and Richman, D.D. (2003) Antiretroviral Drug Resistance Testing in Adults Infected with Human Immunodeficiency Virus Type 1: 2003 Recommendations of an International AIDS Society-USA Panel. Clinical Infectious Diseases, 37, 113-128.

[41]   Soriano, V. and de Mendoza, C. (2002) Genetic Mechanisms of Resistance to Protease Inhibitors and Entry Inhibitors. HIV Clinical Trials, 3, 249-257.

[42]   Peeters, M. and Sharp, P.M. (2000) Genetic Diversity of HIV-1?: The Moving Target. AIDS, 14, S129-S140.

[43]   McCutchan, F.E., Carr, J.K., Bajani, M., Sanders-Buell, E., Harry, T.O., Stoeckli, T.C., Robbins, K.E., Gashau, W., Nasidi, A., Janssens, W. and Kalish, M.L. (1999) Subtype G and Multiple forms of A/G Intersubtype Recombinant Human Immunodeficiency Virus Type 1 in Nigeria. Virology, 254, 226-234.

[44]   Montavon, C., Bibollet-Ruche, F., Robertson, D., Koumare, B., Mulanga, C., Esu-Williams, E., Toure, C., Mboup, S., Saman, E., Delaporte, E. and Peeters, M. (1999) The Identification of a Complex A/G/I/J Recombinant HIV Type 1 Virus in Various West African Countries. AIDS Research and Human Retroviruses, 15, 1707-1712.

[45]   Vergne, L., Bourgeois, A., Mpoudi-Ngole, E., Mougnutou, R., Mbuagbaw, J., Liegeois, F., Laurent, C., Butel, C., Zekeng, L., Delaporte, E. and Peeters, M. (2003) Biological and Genetic Characteristics of HIV Infections in Cameroon Reveals dual Group M and O Infections and a Correlation between SI-Inducing Phenotype of the Predominant CRF02_AG Variant and Disease Stage. Virology, 310, 254-266.

[46]   Lihana, R.W., Ssemwanga, D., Abimiku, A. and Ndembi, N. (2012) Update on HIV-1 Diversity in Africa: A Decade in Review. AIDS Reviews, 14, 83-100.

[47]   Delgado, E., Ampofo, W.K., Sierra, M., Torpey, K., Perez-Alvarez, L., Bonney, E.Y., Mukadi, Y.D., Lartey, M., Nyarko, C., Amenyah, R.N., Thomson, M.M. and Najera, R. (2008) High Prevalence of Unique Recombinant Forms of HIV-1 in Ghana: Molecular Epidemiology from an Antiretroviral Resistance Study. JAIDS Journal of Acquired Immune Deficiency Syndromes, 48, 599-606.