An underestimated lentivirus model: What can HIV-2 research contribute to the development of an effective HIV-1 vaccine?

Expert Review of Anti-Infective Therapy

Volumn 9, Issue 2, 2011, Pages 195-206

  Hodges Mameletzis, Ioannis ^a,b   De Bree, G J ^a   Rowland Jones, Sarah L ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

disease progression; HIV 1; HIV 2; immunopathogenesis; SIV; vaccine development

Indexed keywords

HUMAN IMMUNODEFICIENCY VIRUS VACCINE;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; CERCOCEBUS; CHLOROCEBUS; DISEASE COURSE; EVOLUTIONARY ADAPTATION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS 2; HUMAN IMMUNODEFICIENCY VIRUS 2 INFECTION; IMMUNE RESPONSE; INFECTION CONTROL; MEDICAL RESEARCH; NONHUMAN; PHENOTYPIC VARIATION; REVIEW; SIMIAN IMMUNODEFICIENCY VIRUS; VIRUS LOAD; VIRUS REPLICATION; VIRUS STRAIN;

AIDS VACCINES; ANIMALS; CERCOCEBUS ATYS; CERCOPITHECUS AETHIOPS; DISEASE MODELS, ANIMAL; DISEASE PROGRESSION; HIV INFECTIONS; HIV-1; HIV-2; HUMANS; SIMIAN ACQUIRED IMMUNODEFICIENCY SYNDROME; SIMIAN IMMUNODEFICIENCY VIRUS; SURVIVORS; VIRUS REPLICATION;

EID: 79952138726     PISSN: 14787210     EISSN: 17448336     Source Type: Journal    
DOI: 10.1586/eri.10.176     Document Type: Review

References (108)

1. Piot P, Kazatchkine M, Dybul M, Lob-Levyt J. AIDS: lessons learnt and myths dispelled. Lancet 374(7), 260-263 (2009).
2. Brinkhof MW, Boulle A, Weigel R et al. Mortality of HIV-infected patients starting antiretroviral therapy in sub-Saharan Africa: comparison with HIV-unrelated mortality. PLoS Med. 6(4), e1000066 (2009).
3. Koff WC. Accelerating HIV vaccine development. Nature 464(3), 161-162 (2010).
4. Deeks SG, Walker BD. Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy. Immunity 27(9), 406-416 (2007).
5. Easterbrook PJ, Schrager LK. Long-term nonprogression in HIV infection: methodological issues and scientific priorities. Report of an international European community - National Institutes of Health Workshop, The Royal Society, London, England, November 27-29, 1995. Scientific Coordinating Committee. AIDS Res. Hum. Retroviruses 14(9), 1211-1228 (1998).
6. Okulicz JF, Marconi VC, Landrum ML et al. Clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the US Department of Defense HIV natural history study. J. Infect. Dis. 200(12), 1714-1723 (2009). Clear description of proportions/outcomes of defined subgroups, elite controllers and long-term nonprogressors.
7. Pereyra F, Addo MM, Kaufmann DE et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J. Infect. Dis. 197(2), 563-571 (2008).
8. Baker BM, Block BL, Rothchild AC, Walker BD. Elite control of HIV infection: implications for vaccine design. Expert Opin. Biol. Ther. 9(1), 55-69 (2009).
9. Carrington M, O'Brien SJ. The influence of HLA genotype on AIDS. Annu. Rev. Med. (54), 535-551 (2003).
10. Rowland-Jones SL, Whittle HC. Out of Africa: what can we learn from HIV-2 about protective immunity to HIV-1? Nat. Immunol. 8(4), 329-331 (2007).
11. van der Loeff MF, Larke N, Kaye S et al. Undetectable plasma viral load predicts normal survival in HIV-2-infected people in a West African village. Retrovirology 7(46), 347-352 (2010). First longitudinal study to show that the 'viral controller' phenotype in HIV-2 infection is stable for over a decade.
12. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361(23), 2209-2220 (2009). First HIV Phase III vaccine trial in humans to show protective efficacy.
13. Walker LM, Phogat SK, Chan-Hui PY et al. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326, 285-289 (2009).
14. Zhou, T. Georgiev, I, Wu X et al. Structural basis for the broad and potent neutralization of HIV-1 by antibody VRC01. Science 29(5993), 811-817 (2010).
15. Gao F, Bailes E, Robertson DL et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397(6718), 436-441 (1999).
16. Sodora DL, Allan JS, Apetrei C et al. Toward an AIDS vaccine: lessons from natural simian immunodeficiency virus infections of African nonhuman primate hosts. Nat. Med. 15(8), 861-865 (2009).
17. Wertheim JO, Worobey M. Dating the age of the SIV lineages that gave rise to HIV-1 and HIV-2. PLoS Comput. Biol. 5(5), e1000377 (2009).
18. Clavel F, Guyader M, Gustard D, Sally M, Montagnier L, Alizon M. Molecular cloning and polymorphism of the human immune deficiency virus type 2. Nature 324(6098), 691-695 (1986).
19. Cortes E, Detels R, Aboulafia D et al. HIV-1, HIV-2, and HTLV-I infection in high-risk groups in Brazil. N. Engl. J. Med. 320(15), 953-958 (1989).
20. Ruef C, Dickey P, Schable CA et al. A second case of the acquired immunodeficiency syndrome due to human immunodeficiency virus type 2 in the United States: the clinical implications. Am. J. Med. 86(6 Pt 1), 709-712 (1989).
21. Grez M, Dietrich U, Balfe P et al. Genetic analysis of human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) mixed infections in India reveals a recent spread of HIV-1 and HIV-2 from a single ancestor for each of these viruses. J. Virol. 68(4), 2161-2168 (1994).
22. Schim van der Loeff MF, Aaby P. Towards a better understanding of the epidemiology of HIV-2. AIDS 13(Suppl. A), S69-S84 (1999).
23. Kim SS, Kim EY, Park K et al. Introduction of human immunodeficiency virus 2 infection into South Korea. Acta Virol. 44(1), 15-22 (2000).
24. Bénard A, Damond F, Campa P et al. Good response to lopinavir/ritonavir-containing antiretroviral regimens in antiretroviral-naive HIV-2-infected patients. AIDS 23(9), 1171-1173 (2009).
25. Ibe S, Yokomaku Y, Shiino T et al. HIV-2 CRF01-AB: first circulating recombinant form of HIV-2. J. Acquir. Immune Defic. Syndr. 54(3), 241-247 (2010). First description of a circulating recombinant form of HIV-2 causing significant disease.
26. Valadas E, França L, Sousa S, Antunes F. 20 years of HIV-2 infection in Portugal: trends and changes in epidemiology. Clin. Infect. Dis. 48(8), 1166-1167 (2009).
27. van der Loeff MF, Awasana AA, Sarge-Njie R et al. Sixteen years of HIV surveillance in a West African research clinic reveals divergent epidemic trends of HIV-1 and HIV-2. Int. J. Epidemiol. 35(5), 1322-1328 (2006).
28. Larsen O, da Silva Z, Sandström A et al. Declining HIV-2 prevalence and incidence among men in a community study from Guinea-Bissau. AIDS 12(13), 1707-1714 (1998). An epidemiological survey showing significant decline in prevalence of HIV-2 infection in Guinea-Bissau.
29. van Tienen C, van der Loeff MS, Zaman SM et al. Two distinct epidemics: the rise of HIV-1 and decline of HIV-2 infection between 1990 and 2007 in rural Guinea-Bissau. J. Acquir. Immune Defic. Syndr. 53(5), 640-647 (2010). An epidemiological survey showing significant decline in prevalence of HIV-2 infection in Guinea-Bissau.
30. Damond F, Apetrei C, Robertson DL et al. Variability of human immunodeficiency virus type 2 (HIV-2) infecting patients living in France. Virology 280(1), 19-30 (2001).
31. Hahn BH, Shaw GM, De Cock KM, Sharp PM. AIDS as a zoonosis: scientific and public health implications. Science 287(5453), 607-614 (2000).
32. Yamaguchi J, Devare SG, Brennan CA. Identification of a new HIV-2 subtype based on phylogenetic analysis of full-length genomic sequence. AIDS Res. Hum. Retroviruses 16(9), 925-930 (2000).
33. SM: geographic clustering of household-derived SIV strains with human immunodeficiency virus type 2 subtypes and genetically diverse viruses from a single feral sooty mangabey troop. J. Virol. 70(6), 3617-3627 (1996).
34. Shedlock DJ, Silvestri G, Weiner DB. Monkeying around with HIV vaccines: using rhesus macaques to define 'gatekeepers' for clinical trials. Nat. Rev. Immunol. 9(10), 717-728 (2009).
35. Murphy HW, Miller M, Ramer J et al. Implications of simian retroviruses for captive primate population management and the occupational safety of primate handlers. J. Zoo Wildl. Med. 37(3), 219-233 (2006).
36. Pepin J, Morgan G, Dunn D et al. HIV-2-induced immunosuppression among asymptomatic West African prostitutes: evidence that HIV-2 is pathogenic, but less so than HIV-1. AIDS 5(10), 1165-1172 (1991).
37. Jaffar S, Grant AD, Whitworth J et al. The natural history of HIV-1 and HIV-2 infections in adults in Africa: a literature review. Bull. World Health Organ. 82(6), 462-469 (2004).
38. Hansmann A, Schim van der Loeff MF, Kaye S et al. Baseline plasma viral load and CD4 cell percentage predict survival in HIV-1- and HIV-2-infected women in a community-based cohort in The Gambia. J. Acquir. Immune Defic. Syndr. 38(3), 335-341 (2005).
39. Martinez-Steele E, Awasana AA, Corrah T et al. Is HIV-2- induced AIDS different from HIV-1-associated AIDS? Data from a West African clinic. AIDS 21(3), 317-324 (2007).
40. Schim van der Loeff MF, Jaffar S, Aveika AA et al. Mortality of HIV-1, HIV-2 and HIV-1/HIV-2 dually infected patients in a clinic-based cohort in The Gambia. AIDS 16(13), 1775-1783 (2002).
41. Pandrea I, Silvestri G, Apetrei C. AIDS in African nonhuman primate hosts of SIVs: a new paradigm of SIV infection. Curr. HIV Res. 7(1), 57-72 (2009).
42. Sousa AE, Carneiro J, Meier-Schellersheim M et al. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J. Immunol. 169(6), 3400-3406 (2002). First study to link reduced immune activation to the attenuated disease course of HIV-2 infection.
43. Onyango CO, Leligdowicz A, Yokoyama M et al. HIV-2 capsids distinguish high and low virus load patients in a West African community cohort. Vaccine 28(Suppl. 2), B60-B67 (2010). First description of sequence motifs in HIV-2 capsid that correlate with high or low plasma viral load.
44. + T-cell depletion in HIV infection: are we closer to understanding the cause? Nat. Med. 8(4), 319-323 (2002). Provocative opinion piece relating HIV pathogenesis to immune activation.
45. Silvestri G, Sodora DL, Koup RA et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 18(3), 441-452 (2003). Demonstration that nonprogression in the simian immunodeficiency virus sooty mangabey model is associated with lack of chronic immune activation.
46. Lederer S, Favre D, Walters KA et al. Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog. 5(2), e1000296 (2009).
47. Mandl JN, Barry AP, Vanderford TH et al. Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat. Med. 14(10), 1077-1087 (2008). Study suggesting that lack of immune activation in the simian immunodeficiency virus sooty mangabey model is due to reduced interferon responses to signaling through Toll-like receptors.
48. Kornfeld C, Ploquin MJ, Pandrea I et al. Antiinflammatory profiles during primary SIV infection in African green monkeys are associated with protection against AIDS. J. Clin. Invest. 115(4), 1082-1091 (2005).
49. AGM dynamics in African green monkeys. J. Virol. 82(7), 3713-3724 (2008).
50. Schindler M, Münch J, Kutsch O et al. Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 125(6), 1055-1067 (2006). Major study showing that the nef genes of nonpathogeneic retroviruses differ from those of pathogenic strains in their ability to downregulate the T-cell receptor complex, thereby reducing excessive immune activation.
51. Jaffar S, Van der Loeff MS, Eugen-Olsen J et al. Immunological predictors of survival in HIV type 2-infected rural villagers in Guinea-Bissau. AIDS Res. Hum. Retroviruses 21(6), 560-564 (2005).
52. Leligdowicz A, Feldmann J, Jaye A et al. Direct relationship between virus load and systemic immune activation in HIV-2 infection. J. Infect. Dis. 201(1), 114-122 (2010).
53. Feldmann J, Leligdowicz A, Jaye A et al. Downregulation of the T-cell receptor by human immunodeficiency virus type 2 Nef does not protect against disease progression. J. Virol. 83(24), 12968-12972 (2009). Study showing that different degrees of T-cell receptor downregulation by HIV-2 Nef correlates with immune activation but not with disease status.
54. + T cells in multiple tissues during acute SIV infection. Nature 434(7037), 1093-1097 (2005).
55. Brenchley JM, Price DA, Schacker TW et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12(12), 1365-1371 (2006).
56. Nowroozalizadeh S, Månsson F, da Silva Z et al. Microbial translocation correlates with the severity of both HIV-1 and HIV-2 infections. J. Infect. Dis. 201(8), 1150-1154 (2010). First study of microbial translocation in both HIV-1 and HIV-2 infections.
57. Brass AL, Dykxhoorn DM, Benita Y et al. Identification of host proteins required for HIV infection through a functional genomic screen. Science 319(5865), 921-926 (2008).
58. Wiegand HL, Doehle BP, Bogerd HP, Cullen BR. A second human antiretroviral factor, APOBEC3F, is suppressed by the HIV-1 and HIV-2 Vif proteins. EMBO J. 23(12), 2451-2458 (2004).
59. Ribeiro AC, Maia e Silva A, Santa-Marta M et al. Functional analysis of Vif protein shows less restriction of human immunodeficiency virus type 2 by APOBEC3G. J. Virol. 79(2), 823-833 (2005).
60. Holmes RK, Malim MH, Bishop KN. APOBEC-mediated viral restriction: not simply editing? Trends Biochem. Sci. 32(3), 118-128 (2007).
61. MAC by TRIM5α alleles. J. Virol. 79(18), 11580-11587 (2005).
62. Song H, Nakayama EE, Yokoyama M et al. A single amino acid of the human immunodeficiency virus type 2 capsid affects its replication in the presence of cynomolgus monkey and human TRIM5αs. J. Virol. 81(13), 7280-7285 (2007).
63. Lim SY, Rogers T, Chan T et al. TRIM5α modulates immunodeficiency virus control in rhesus monkeys. PLoS Pathog. 6(1), e1000738 (2010).
64. Nuvor SV, van der Sande M, Rowland-Jones S et al. Natural killer cell function is well preserved in asymptomatic human immunodeficiency virus type 2 (HIV-2) infection but similar to that of HIV-1 infection when CD4 T-cell counts fall. J. Virol. 80(5), 2529-2538 (2006).
65. + T cell help distinguishes HIV-2 from HIV-1 infection. J. Immunol. 176(11), 6973-6981 (2006).
66. Duvall MG, Precopio ML, Ambrozak DA et al. Polyfunctional T cell responses are a hallmark of HIV-2 infection. Eur. J. Immunol. 38(2), 350-363 (2008). Demonstration of preserved T-cell help in HIV-2 infection.
67. Leligdowicz A, Yindom LM, Onyango C et al. Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection. J. Clin. Invest. 117(10), 3067-3074 (2007). Shows a clear inverse correlation between HIV-2 viral load and the magnitude of the HIV-specific T-cell response and describes protective T-cell responses to a conserved region of HIV-2 gag.
68. +) T-cells in chronic HIV-2 infection. Eur. J. Immunol. 1963-1972 (2010).
69. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF. The immune response during acute HIV-1 infection: clues for vaccine development. Nat. Rev. Immunol. 10(1), 11-23 (2010).
70. + T-cell recognition occurs within weeks of the primary infection.
71. + T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection. Retrovirology 5, 112 (2008).
72. Kelleher AD, Long C, Holmes EC et al. Clustered mutations in HIV-1 Gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J. Exp. Med. 193(3), 375-386 (2001).
73. + T-cell responses to different HIV proteins have discordant associations with viral load. Nat. Med. 13(1), 46-53 (2007). First demonstration that multiple gag-specific T-cell responses correlate with lower viral load in HIV-1 infection.
74. +) T-cell responses: relationship to viral load in untreated HIV infection. J. Virol. 75(24), 11983-11991 (2001).
75. Addo MM, Yu XG, Rathod A et al. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)- specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses, but no correlation to viral load. J. Virol. 77(3), 2081-2092 (2003).
76. + T cells in HIV-infected progressors and long-term nonprogressors. J. Immunol. 165(2), 1082-1092 (2000).
77. + T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8(4), 379-385 (2002).
78. + T cells: diversity specialists. Immunol. Rev. 211, 225-235 (2006). First description of distinct differentiation phenotypes in the CD8+ T-cell responses to different viruses.
79. + T cells specific for influenza A viruses. J. Infect. Dis. 187(7), 1075-1084 (2003).
80. Champagne P, Ogg GS, King AS et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410(6824), 106-111 (2001).
81. + T cell responses to human immunodeficiency viruses type 2 (HIV-2) and type 1 (HIV-1) Gag proteins are distinguishable by magnitude and breadth but not cellular phenotype. Eur. J. Immunol. 35(5), 1445-1453 (2005).
82. Leligdowicz A, Feldmann J, Jaye A et al. Direct relationship between virus load and systemic immune activation in HIV-2 infection. J. Infect. Dis. 201(1), 114-122 (2010).
83. Tesselaar K, Xiao Y, Arens R et al. Expression of the murine CD27 ligand CD70 in vitro and in vivo. J. Immunol. 170(1), 33-40 (2003).
84. + T-cells from viral controllers have higher perforin expression.
85. Betts MR, Exley B, Price DA et al. Characterization of functional and phenotypic changes in anti-Gag vaccine-induced T cell responses and their role in protection after HIV-1 infection. Proc. Natl Acad. Sci. USA 102(12), 4512-4517 (2005).
86. Shi Y, Brandin E, Vincic E et al. Evolution of human immunodeficiency virus type 2 coreceptor usage, autologous neutralization, envelope sequence and glycosylation. J. Gen. Virol. 86(Pt 12), 3385-3396 (2005).
87. Duvall MG, Loré K, Blaak H et al. Dendritic cells are less susceptible to human immunodeficiency virus type 2 (HIV-2) infection than to HIV-1 infection. J. Virol. 81(24), 13486-13498 (2007). Study showing that blood dendritic cells are resistant to HIV-2 infection in vitro.
88. + T cells are preferentially infected by the virus.
89. SMM infection of macaque and mangabey monkeys: correlation between in vivo and in vitro properties of different isolates. Dev. Biol. Stand. 72, 253-258 (1990).
90. Weiss RA, Clapham PR, McClure MO et al. Immunodeficiency viruses: neutralization and receptors. J. Acquir. Immune Defic. Syndr. 1(6), 536-541 (1988).
91. Björling E, Scarlatti G, von Gegerfelt A et al. Autologous neutralizing antibodies prevail in HIV-2 but not in HIV-1 infection. Virology 193(1), 528-530 (1993).
92. de Silva TI, Cotten M, Rowland-Jones SL. HIV-2: the forgotten AIDS virus. Trends Microbiol. 16(12), 588-595 (2008).
93. Rodriguez SK, Sarr AD, MacNeil A et al. Comparison of heterologous neutralizing antibody responses of human immunodeficiency virus type 1 (HIV-1)-and HIV-2-infected Senegalese patients: distinct patterns of breadth and magnitude distinguish HIV-1 and HIV-2 infections. J. Virol. 81(10), 5331-5338 (2007).
94. Yindom LM, Leligdowicz A, Martin MP et al. Influence of HLA class I and HLA-KIR compound genotypes on HIV-2 infection and markers of disease progression in a Manjako community in West Africa. J. Virol. 84(16), 8202-8208 (2010).
95. Allsop CE, Harding RM, Taylor C et al. Interethnic genetic differentiation in Africa: HLA class I antigens in The Gambia. Am. J. Hum. Genet. 50(2), 411-421 (1992).
96. Burgard M, Jasseron C, Matheron S et al. Mother-to-child transmission of HIV-2 infection from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1. Clin. Infect. Dis. 51(7), 833-843 (2010).
97. Padua E, Jenkins A, Brown S et al. Natural variation of the nef gene in human immunodeficiency virus type 2 infections in Portugal. J. Gen. Virol. 84(Pt 5), 1287-1299 (2003).
98. Blaak H, van der Ende ME, Boers PH et al. In vitro replication capacity of HIV-2 variants from long-term aviremic individuals. Virology 353(1), 144-154 (2006).
99. Gurjar SR, Mangaiarkarasi A, Ravi V et al. Molecular characterization of a full-length genome of a HIV-2 isolate from India. J. Acquir. Immune Defic. Syndr. 52(3), 329-335 (2009).
100. Jadhav S, Tripathy S, Kulkarni S et al. Molecular phylogenetics of nearly full-length HIV type 2 envelope gene sequences from West India. AIDS Res. Hum. Retroviruses 25(1), 115-121 (2009).
101. Santhosh CV, Tamhane MC, Mukhopadhyaya R, Mukhopadhyaya R. Full-length genome characterization of an HIV type 2 isolate from India. AIDS Res. Hum. Retroviruses 24(10), 1315-1317 (2008).
102. Fujita M, Otsuka M, Miyoshi M et al. Vpx is critical for reverse transcription of the human immunodeficiency virus type 2 genome in macrophages. J. Virol. 82(15), 7752-7756 (2008).
103. Khamsri B, Murao F, Yoshida A et al. Comparative study on the structure and cytopathogenic activity of HIV Vpr/Vpx proteins. Microbes Infect. 8(1), 10-15 (2006).
104. Morikawa Y, Goto T, Yasuoka D et al. Defect of human immunodeficiency virus type 2 Gag assembly in Saccharomyces cerevisiae. J. Virol. (18), 9911-9921 (2007).
105. Gottlieb GS, Eholié SP, Nkengasong JN et al. A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS 22(16), 2069-2072 (2008).
106. Keele BF, Giorgi EE, Salazar-Gonzalez JF et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl Acad. Sci. USA 105(21), 7552-7557 (2008).
107. Barouch DH. Challenges in the development of an HIV-1 vaccine. Nature 455(10), 613-619 (2008).
108. HIV Vaccines and Microbicides Resource Tracking Working Group. Adapting to Realities: Trends in HIV Prevention Research Funding 2000 to 2008 www.hivresourcetracking.org