Biopolym. Cell. 2004; 20(3):171-181.
The problems of variability of the human immunodeficiency virus
1Ivans'ka N. V., 1Trokhimchuk T. Yu.
  1. Gromashevsky L.V. Institute of Epidemiology and Infection Diseases, AMS of Ukraine
    5, Amosova Str., Kyiv, Ukraine, 03038


This review deals with variability of the human immunodeficiency virus (HIV) and the epidemiological consequences of such variability. The level of the HIV variability is extremely high. For example, the mutation frequency determined for the HIV gene env is ten times higher comparing to the variability of the influenza virus which had been thought to be the most variable before investigations carried on the HIV variability. The information concerning the HIV variability problem is useful for studies on epidemiological control of the HIV-infection and the choice of anti-AIDS strategy; the data obtained are also necessary to construct therapeutic and preventive vaccines as well as reliable diagnostic test-systems.


[1] Saag MS, Hahn BH, Gibbons J, Li Y, Parks ES, Parks WP, Shaw GM. Extensive variation of human immunodeficiency virus type-1 in vivo. Nature. 1988;334(6181):440-4.
[2] Mansky LM, Temin HM. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol. 1995;69(8):5087-94.
[3] Kevlova H, Liitsola K, Smol'skaya T, Korovina G, Markevich N, Tashkinova IP. Continued research on the molecular characterization of strains that caused the HIV epidemic in the Kaliningrad region. Rus zhurn VICH/SPID i rodstv problemy. 2000; 4(1):63-4.
[4] Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature. 1998;391(6667):594-7.
[5] Masharskiy AE, Nabatov AA, Verevochkin SV, Murashev BV, Kozlov AP. Cloning of fragments of the genome of HIV-1 variants circulating in the countries of the former Soviet Union, for an HIV vaccine. Rus. zhurn. VICH/SPID i rodstv problemy. 2000; 4(1):25-6.
[6] Delwart EL, Shpaer EG, Louwagie J, McCutchan FE, Grez M, R?bsamen-Waigmann H, Mullins JI. Genetic relationships determined by a DNA heteroduplex mobility assay: analysis of HIV-1 env genes. Science. 1993;262(5137):1257-61.
[7] Khaitov PM, Ignat'yeva GA. AIDS. Moscow, NAHIOTS, 1992; 352 p.
[8] Gao F, Yue L, Robertson DL, Hill SC, Hui H, Biggar RJ, Neequaye AE, Whelan TM, Ho DD, Shaw GM, et al. Genetic diversity of human immunodeficiency virus type 2: evidence for distinct sequence subtypes with differences in virus biology. J Virol. 1994;68(11):7433-47.
[9] Kazennova EV, Bobkov AF, Selimova LM, Khanina TA, Pokrovskii VV, Heyndrickx L, Van der Groen G. Analysis of gag gene subtypes of HIV-1 variants isolated in Russia by comparative assessment of heteroduplex electrophoretic mobility]. Vopr Virusol. 2001;46(3):12-6.
[10] Bobkova MR, Kazennova EV, Selimova LM, Buravtsova EV, Lister S, Prilipov AG, Weber JN, Pokrovsky VV, Bobkov AF. Serological approaches to subtyping of HIV-1 in injecting drug users in Russia: evidence of subtype homogeneity at the main sites of the epidemic. Int J STD AIDS. 2001;12(1):34-40.
[11] Reymers HF. Popular Dictionary of Biology. Moscow, Nauka, 1991; 216 p.
[12] Osmanov S., HIV type 1 variation in World Health Organization-sponsored vaccine evaluation sites: genetic screening, sequence analysis, and preliminary biological characterization of selected viral strains. WHO Network for HIV Isolation and Characterization. AIDS Res Hum Retroviruses. 1994;10(11):1327-43.
[13] Karamov EV, Shchelkanov MIu, Iudin AN, Gorbacheva AP, Burunova VV, Slavski? AA, Lukashov VV, Iaroslavtseva NG. The molecular epidemiological characteristics of the HIV-1 variants circulating among injection drug addicts on the territory of the CIS Nations. Zh Mikrobiol Epidemiol Immunobiol. 1999; 1:39-41.
[14] Komissarenko SV. Immunological recognition of antigenic determinants of proteins and peptides. Ukr Biokhim Zh. 1985;57(5):50-62.
[15] Pashkova TA, Iaroslavtseva NG, Shchelkanov MIu, Papuashvili MN, Sakhuriia IB, Kornilaeva GV, Karamov EV. Biological properties of primary HIV-1 isolates with varying serotype. Vopr Virusol. 1998;43(6):256-61.
[16] Nosik DN. Creating a collection of human immunodeficiency virus circulating in the Russian Federation: Author. dis. ... Dr. biol. Sciences. M., 1992; 79 p.
[17] Barinskii IF, Nosik DN, Kal'nov SL, Nikitina AA, L'vov ND, Petrova MS, Tsibezov VV. Activation of viral reproduction in a mixed infection with human immunodeficiency virus and herpes viruses. Vopr Virusol. 1994;39(5):223-6.
[18] Barbasheva YeV. Study the biological properties of the first type of immunodeficiency viruses isolated in Ukraine: Author. dis. ... kand. med. nauk. Kiev, 1997; 18 p.
[19] Karlsson I, Antonsson L, Shi Y, Karlsson A, Albert J, Leitner T, Olde B, Owman C, Fenyo EM. HIV biological variability unveiled: frequent isolations and chimeric receptors reveal unprecedented variation of coreceptor use. AIDS. 2003;17(18):2561-9.
[20] Pokrovskiy VV, Yermak TN, Belyayeva VV, Yurin OG. HIV infection: clinical features, diagnosis and treatment. Moscow, Geotar Medicine, 2000. 489 p.
[21] Tsilinskiy YaYa. Population structure and evolution of viruses. Moscow, Medicine, 1988; 240 p.
[22] Bukrinskaya AG. Human immunodeficiency virus: addition to the author's text. Evolution of viruses. Ed. VM. Zhdanov. Moscow, Medicine, 1988; 225-37.
[23] Antoni BA, Stein SB, Rabson AB. Regulation of human immunodeficiency virus infection: implications for pathogenesis. Adv Virus Res. 1994;43:53-145.
[24] Javaherian K, Langlois AJ, McDanal C, Ross KL, Eckler LI, Jellis CL, Profy AT, Rusche JR, Bolognesi DP, Putney SD, et al. Principal neutralizing domain of the human immunodeficiency virus type 1 envelope protein. Proc Natl Acad Sci U S A. 1989;86(17):6768-72.
[25] Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev. 1993;57(1):183-289.
[26] Fisher AG, Ensoli B, Looney D, Rose A, Gallo RC, Saag MS, Shaw GM, Hahn BH, Wong-Staal F. Biologically diverse molecular variants within a single HIV-1 isolate. Nature. 1988;334(6181):444-7.
[27] Terwilliget E.F., Langhoff E., Haseltine W. Characterization of HIV-1 accessory regulatory gene effects upon virus replication in primary cell population. J. Cell. Biochem., 1992; (SUPPL. 16):57.
[28] Rubsamen-Waigmann H, von Briesen H, Holmes H, Bjorndal A, Korber B, Esser R, Ranjbar S, Tomlinson P, Galvao-Castro B, Karita E, et al. Standard conditions of virus isolation reveal biological variability of HIV type 1 in different regions of the world. WHO Network for HIV Isolation and Characterization. AIDS Res Hum Retroviruses. 1994;10(11):1401-8.
[29] Bukrinskaya AG, Zhdanov VM. Molecular basis of viral pathogenicity. Moscow, Medicine, 1991. 256 p.
[30] Polyanova M. Genetic diversity in HIV viruses strains - the main problem in successful vaccine creation. Infektologiya. 1999; 36 (4) :3-8.
[31] Delwart EL, Herring B, Rodrigo AG, Mullins JI. Genetic subtyping of human immunodeficiency virus using a heteroduplex mobility assay. PCR Methods Appl. 1995;4(5):S202-16.
[32] Soares MA, De Oliveira T, Brindeiro RM, Diaz RS, Sabino EC, Brigido L, Pires IL, Morgado MG, Dantas MC, Barreira D, Teixeira PR, Cassol S, Tanuri A; Brazilian Network for Drug Resistance Surveillance. A specific subtype C of human immunodeficiency virus type 1 circulates in Brazil. AIDS. 2003;17(1):11-21.
[33] Gessain A, Mahieux R. A virus called HTLV-1. Epidemiological aspects. Presse Med. 2000;29(40):2233-9.
[34] Hlozanek I, Rynditch AV, Mikhailik A. Role of replaced v-src and env genes in the duck-adapted variant of Rous sarcoma virus. Folia Biol (Praha). 1993;39(4):203-10.
[35] Mykhaylyk AA. Formation of new viruses in birds sarcoma src proto-oncogene transduction and adaptation to nonspecific host: Author. Thesis. ... Candidate. Biol. nauk. Kyiv, 1994. 26 p.
[36] Popovic M, Read-Connole E, Gartner S. Biological properties of HTLV-III/LAV: a possible pathway of natural infection in vivo. Ann Inst Pasteur Immunol. 1986;137D(3):413-7.
[37] Selimova LM, Kliushnik SIu. A comparison of 2 T-lymphoid cell lines persistently infected with the human immunodeficiency virus (HIV-1) with different productive capacities. Vopr Virusol. 1991;36(4):277-81.
[38] Poffenberger K.L., Riordan L., Lee S. Persistent HIV-1 (MN) infection of mammary epithelial cells in vitro. J. Cell. Biochem., 1993; (SUPPL. 17):36.
[39] Robertson DL, Sharp PM, McCutchan FE, Hahn BH. Recombination in HIV-1. Nature. 1995;374(6518):124-6.
[40] Takebe Y, Motomura K, Tatsumi M, Lwin HH, Zaw M, Kusagawa S. High prevalence of diverse forms of HIV-1 intersubtype recombinants in Central Myanmar: geographical hot spot of extensive recombination. AIDS. 2003;17(14):2077-87.
[41] Oh MD, Choe K. Epidemiology of HIV infection in the Republic of Korea. J Korean Med Sci. 1999;14(5):469-74.
[42] Chang K.H. Characteristics of HIV infection/AIDS in Korea. AIDS DNA Vaccine Conf. and Workshop: Perspectives of the Preventive and Therapeutic HIV-1 Vaccines, New York, 2002 p. 128.
[43] Bobkov AF, Kazennova EV, Selimova LM, Momot OF, Ladnaia NN, Bobkova MR, Pokrovskii VV. Recombinant human immunodeficiency viruses. Zh Mikrobiol Epidemiol Immunobiol. 1999;(1):45-7.
[44] Deroo S, Robert I, Fontaine E, Lambert C, Pless?ria JM, Arendt V, Staub T, Hemmer R, Schneider F, Schmit JC. HIV-1 subtypes in Luxembourg, 1983-2000. AIDS. 2002;16(18):2461-7.
[45] Bobkov AF, Kazennova EV, Selimova LM, Ladnaia NN, Bobkova MR, Kravchenko AV, Pokrovskii VV. HIV-1 subtypes in Russia in 1987-1988. Zh Mikrobiol Epidemiol Immunobiol. 1999;(1):43-5.
[46] Bobkov AF, Pokrovskii VV, Selimova LM, Ladnaia NN, Kazennova EV, Bobkova MR, Khanina TA, Kravchenko AV, Iurin OG, Saukhat SR. Genetic characteristics of variants of human immunodeficiency virus type 1, causing an epidemic among substance abusers in Commonwealth of Independent States countries. Vopr Virusol. 1998;43(6):253-6.
[47] Kozlov AP. HIV in Russia, Belarus and Ukraine. Rus. zhurn. VICH/SPID i rodstv. problemy. 2000; 4(1):11-4.
[48] Korovina GI, Smol'skaia TT, Tashkinova IP, Momot OF, Kevlova NA, Liitsola K, Leinikki P, Salminen M. A recombinant HIV-1 strain causing an epidemic among injection drug addicts in Kaliningrad. Zh Mikrobiol Epidemiol Immunobiol. 1999;(1):47-9.
[49] Keys B, Karis J, Fadeel B, Valentin A, Norkrans G, Hagberg L, Chiodi F. V3 sequences of paired HIV-1 isolates from blood and cerebrospinal fluid cluster according to host and show variation related to the clinical stage of disease. Virology. 1993;196(2):475-83.
[50] Cheng-Mayer C, Weiss C, Seto D, Levy JA. Isolates of human immunodeficiency virus type 1 from the brain may constitute a special group of the AIDS virus. Proc Natl Acad Sci U S A. 1989;86(21):8575-9.
[51] Zhang LQ, MacKenzie P, Cleland A, Holmes EC, Brown AJ, Simmonds P. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol. 1993;67(6):3345-56.
[52] Gomez Carrillo M, Piccardo C, Libonatti O. Molecular analysis of the principal neutralization epitope (V3 loop) of human immunodeficiency virus type 1 in Argentina. Rev Argent Microbiol. 1992;24(2):91-101.
[53] Garayev MM. Laws variability main dominant neutralizing human immunodeficiency virus: Author. dis. ... Cand. biol. nauk. Moscow, 1993. 48 p.
[54] Gomez-Carillo M., Piccardo C, Libonatti O. Molecular analysis of the principal neutralization epitope (V3 loop) of human immunodeficiency virus type 1 in Argentina. Rev Argent Microbiol. 1992;24(2):91-101.
[55] Zwart G, Wolfs TF, Bookelman R, Hartman S, Bakker M, Boucher CA, Kuiken C, Goudsmit J. Greater diversity of the HIV-1 V3 neutralization domain in Tanzania compared with The Netherlands: serological and genetic analysis. AIDS. 1993;7(4):467-74.
[56] Tersmette M, Gruters RA, de Wolf F, de Goede RE, Lange JM, Schellekens PT, Goudsmit J, Huisman HG, Miedema F. Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates. J Virol. 1989;63(5):2118-25.
[57] Wain-Hobson S. Human immunodeficiency virus type 1 quasispecies in vivo and ex vivo. Curr Top Microbiol Immunol. 1992;176:181-93.
[58] Sampalo Lainz A, Lopez-Gomez M. From HIV infection to AIDS: immunobiologic mechanisms. Med Clin (Barc). 1994;103(12):454-7.
[59] Roulston A, Lin R, Beauparlant P, Wainberg MA, Hiscott J. Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors. Microbiol Rev. 1995;59(3):481-505.
[60] Nosik DM, Bochkova MC, Kiseleva IA. Guidelines on human immunodeficiency virus isolation from HIV-infected persons and patients AIDS. Methods in Molecular, general and medical virology: Proc. Inst of Virology named of DI Ivanovsky. Moscow, 1992:170-9.
[61] Cheng-Mayer C, Quiroga M, Tung JW, Dina D, Levy JA. Viral determinants of human immunodeficiency virus type 1 T-cell or macrophage tropism, cytopathogenicity, and CD4 antigen modulation. J Virol. 1990;64(9):4390-8.
[62] Goodenow M, Huet T, Saurin W, Kwok S, Sninsky J, Wain-Hobson S. HIV-1 isolates are rapidly evolving quasispecies: evidence for viral mixtures and preferred nucleotide substitutions. J Acquir Immune Defic Syndr. 1989;2(4):344-52.
[63] Meyerhans A, Cheynier R, Albert J, Seth M, Kwok S, Sninsky J, Morfeldt-Manson L, Asjo B, Wain-Hobson S. Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations. Cell. 1989;58(5):901-10.
[64] Holland JJ, De La Torre JC, Steinhauer DA. RNA virus populations as quasispecies. Curr Top Microbiol Immunol. 1992;176:1-20.
[65] Connor RI, Notermans DW, Mohri H, Cao Y, Ho DD. Biological cloning of functionally diverse quasispecies of HIV-1. AIDS Res Hum Retroviruses. 1993;9(6):541-6.
[66] Sharp P.M., Robertson D.L., Gao F., Hahn B.H. Origins and diversity of human immunodeficiency viruses. AIDS, 1994; 8 (SUPPL. 1), pp. S27-S42.
[67] Fredriksson R, Stalhanske P, von Gegerfelt A, Lind B, Aman P, Rassart E, Fenyo EM. Biological characterization of infectious molecular clones derived from a human immunodeficiency virus type-1 isolate with rapid/high replicative capacity. Virology. 1991;181(1):55-61.
[68] Shioda T, Oka S, Ida S, Nokihara K, Toriyoshi H, Mori S, Takebe Y, Kimura S, Shimada K, Nagai Y, et al. A naturally occurring single basic amino acid substitution in the V3 region of the human immunodeficiency virus type 1 env protein alters the cellular host range and antigenic structure of the virus. J Virol. 1994;68(12):7689-96.
[69] Poss M, Martin HL, Kreiss JK, Granville L, Chohan B, Nyange P, Mandaliya K, Overbaugh J. Diversity in virus populations from genital secretions and peripheral blood from women recently infected with human immunodeficiency virus type 1. J Virol. 1995;69(12):8118-22.
[70] Andersson B., Gibbs R.A. Examination of HIV-1 proviral sequence diversity using denaturating gradient gel electrophoresis reveals dominant forms within patient samples. J Cell Biochem., 1993 (SUPPL. 17):73.
[71] Bou-Habib DC, Roderiquez G, Oravecz T, Berman PW, Lusso P, Norcross MA. Cryptic nature of envelope V3 region epitopes protects primary monocytotropic human immunodeficiency virus type 1 from antibody neutralization. J Virol. 1994;68(9):6006-13.
[72] Pokrovskiy VV. Epidemiology and prevention of HIV infection and AIDS. Moscow, Medicine, 1996. 248 p.
[73] Bushman F, Landau NR, Emini EA. New developments in the biology and treatment of HIV. Proc Natl Acad Sci U S A. 1998;95(19):11041-2.
[74] Murashev BV, Romanovich AE, Murashva IV, Masharskiy AE, Klimov NA, Kozlov AP. Creating, monitoring and biological testing of DNA vaccines. Rus. zhurn. VICH/SPID i rodstv. problemy. 2000; 4(1):26-7.
[75] Antonyak S. Report on the pilot study with DNA vaccine (GX-1, GX-12) in 20 HIV-infected subjects to investigate efficacy and safety in combination with HAART. AIDS DNA Vaccine Conf. and Workshop: Perspectives of the Preventive and Therapeutic HIV-1 Vaccines, New York. 2002;135-136.
[76] Oliynyk I. Pilot study with DNA-vaccines (GX-1, GX-la and GX-12) in 20 HIV-infected subjects to investigate efficacy and safety in combination with HAART therapy GB-203.AIDS DNA Vaccine Conf. and Workshop: Perspectives of the Preventive and Therapeutic HIV-1 Vaccines, 2002:138.
[77] Eum S.-Y. Therapeutic vaccination with DNA priming and adenovirus boosting strategy in chronically HIV-infected chimpanzee () AIDS DNA Vaccine Conf. and Workshop: Perspectives of the Preventive and Therapeutic HIV-1 Vaccines, New York. 2002: 18
[78] Alizon M, Wain-Hobson S, Montagnier L, Sonigo P. Genetic variability of the AIDS virus: nucleotide sequence analysis of two isolates from African patients. Cell. 1986;46(1):63-74.
[79] Korber B., Brander C., Haynes B., Moore J., Koup R., Walker B., Watkins D. HIV molecular immunology database. Los Alamos: Nat. Lab. Publ., 1999:352.
[80] Castro BA, Barnett SW, Evans LA, Moreau J, Odehouri K, Levy JA. Biologic heterogeneity of human immunodeficiency virus type 2 (HIV-2) strains. Virology. 1990;178(2):527-34.