Phenotypic characterisation of Human Immunodeficiency Virus type 1 Envelope entry efficiency of transmitted/founder variants circulating in Mbeya, Tanzania

Main Article Content

Zenda Loren Woodman Philippe Selhorst‎ Andile Nofemela Gama Bandawe Michael Hoelscher Leonard Maboko Jinny Marais


Background:  Altered fitness of transmitted founder (T/F) HIV-1 variants has been linked to slowed disease progression, yet almost all of these studies have focussed on the role of attenuating immune escape mutations in T/F Gag or entry efficiency of Envelope (Env) in long-term non-progressors (LTNP) and elite suppressors (ES) during chronic stages of infection. As Env could also play an important role in viral fitness during early infection, we investigated if T/F Env entry efficiency, prior to immune selection, affected viral loads of progressors in vivo.  

Findings: Functional Env clones from eight progressors and one LTNP, representing the T/F virus responsible for clinical infection, were constructed. Subsequently Env pseudoviruses (PSVs) were generated, and confirmed to be all R5 but not macrophage tropic. PSVs had a ~80 fold range in entry efficiencies using TZM-bl cells with the LTNP being the poorest enterer. Enhanced entry was associated with increased viral load at 3 months although this association was reduced by 12 months. Finally, we show that entry efficiency was influenced by fusion capacity, CCR5/CD4 dependency, and/or incorporation of gp120 into pseudovirions.

Conclusion:  The variation in TZM-bl entry efficiency of T/F viruses was due to one or more advantageous Env attributes. Viruses with high entry efficiency may have a replication advantage subsequent to transmission, leading to increased viral loads during early infection of progressors.

Article Details

How to Cite
WOODMAN, Zenda Loren et al. Phenotypic characterisation of Human Immunodeficiency Virus type 1 Envelope entry efficiency of transmitted/founder variants circulating in Mbeya, Tanzania. Medical Research Archives, [S.l.], v. 2, n. 2, sep. 2015. ISSN 2375-1924. Available at: <>. Date accessed: 19 may 2024.
HIV, transmission, entry efficiency, disease progression
Research Articles


1. Abrahams, M. R., J. A. Anderson, E. E. Giorgi, C. Seoighe, K. Mlisana, L. H. Ping, G. S. Athreya, F. K. Treurnicht, B. F. Keele, N. Wood, J. F. Salazar-Gonzalez, T. Bhattacharya, H. Chu, I. Hoffman, S. Galvin, C. Mapanje, P. Kazembe, R. Thebus, S. Fiscus, W. Hide, M. S. Cohen, S. A. Karim, B. F. Haynes, G. M. Shaw, B. H. Hahn, B. T. Korber, R. Swanstrom, C. Williamson, C. A. I. S. Team and H. I. V. A. V. I. C. Center for (2009). "Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants." J Virol 83(8): 3556-3567.
2. Alexander, M., R. Lynch, J. Mulenga, S. Allen, C. A. Derdeyn and E. Hunter (2010). "Donor and recipient envs from heterosexual human immunodeficiency virus subtype C transmission pairs require high receptor levels for entry." J Virol 84(8): 4100-4104.
3. Bachrach, E., H. Dreja, Y. L. Lin, C. Mettling, V. Pinet, P. Corbeau and M. Piechaczyk (2005). "Effects of virion surface gp120 density on infection by HIV-1 and viral production by infected cells." Virology 332(1): 418-429.
4. Ball, S. C., A. Abraha, K. R. Collins, A. J. Marozsan, H. Baird, M. E. Quinones-Mateu, A. Penn-Nicholson, M. Murray, N. Richard, M. Lobritz, P. A. Zimmerman, T. Kawamura, A. Blauvelt and E. J. Arts (2003). "Comparing the Ex Vivo Fitness of CCR5-Tropic Human Immunodeficiency Virus Type 1 Isolates of Subtypes B and C." Journal of Virology 77(2): 1021-1038.
5. Burgers, W. A., J. H. van Harmelen, E. Shephard, C. Adams, T. Mgwebi, W. Bourn, T. Hanke, A. L. Williamson and C. Williamson (2006). "Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial." J Gen Virol 87(Pt 2): 399-410.
6. Casado, C., S. Colombo, A. Rauch, R. Martinez, H. F. Gunthard, S. Garcia, C. Rodriguez, J. Del Romero, A. Telenti and C. Lopez-Galindez (2010). "Host and viral genetic correlates of clinical definitions of HIV-1 disease progression." PLoS One 5(6): e11079.
7. Casado, C., M. Pernas, V. Sandonis, T. Alvaro-Cifuentes, I. Olivares, R. Fuentes, L. Martinez-Prats, E. Grau, L. Ruiz, R. Delgado, C. Rodriguez, J. del Romero and C. Lopez-Galindez (2013). "Identification of a cluster of HIV-1 controllers infected with low replicating viruses." PLoS One 8(10): e77663.
8. Chopera, D. R., Z. Woodman, K. Mlisana, M. Mlotshwa, D. P. Martin, C. Seoighe, F. Treurnicht, D. A. de Rosa, W. Hide, S. A. Karim, C. M. Gray, C. Williamson and C. S. Team (2008). "Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage." PLoS Pathog 4(3): e1000033.
9. Cilliers, T., P. Moore, M. Coetzer and L. Morris (2005). "In vitro generation of HIV type 1 subtype C isolates resistant to enfuvirtide." AIDS Res Hum Retroviruses 21(9): 776-783.
10. Fouda, G. G., T. Mahlokozera, J. F. Salazar-Gonzalez, M. G. Salazar, G. Learn, S. B. Kumar, S. M. Dennison, E. Russell, K. Rizzolo, F. Jaeger, F. Cai, N. A. Vandergrift, F. Gao, B. Hahn, G. M. Shaw, C. Ochsenbauer, R. Swanstrom, S. Meshnick, V. Mwapasa, L. Kalilani, S. Fiscus, D. Montefiori, B. Haynes, J. Kwiek, S. M. Alam and S. R. Permar (2013). "Postnatally-transmitted HIV-1 Envelope variants have similar neutralization-sensitivity and function to that of nontransmitted breast milk variants." Retrovirology 10: 3.
11. Goepfert, P. A., W. Lumm, P. Farmer, P. Matthews, A. Prendergast, J. M. Carlson, C. A. Derdeyn, J. Tang, R. A. Kaslow, A. Bansal, K. Yusim, D. Heckerman, J. Mulenga, S. Allen, P. J. Goulder and E. Hunter (2008). "Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients." J Exp Med 205(5): 1009-1017.
12. Haaland, R. E., P. A. Hawkins, J. Salazar-Gonzalez, A. Johnson, A. Tichacek, E. Karita, O. Manigart, J. Mulenga, B. F. Keele, G. M. Shaw, B. H. Hahn, S. A. Allen, C. A. Derdeyn and E. Hunter (2009). "Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1." PLoS Pathog 5(1): e1000274.
13. Herbinger, K. H., M. Gerhardt, S. Piyasirisilp, D. Mloka, M. A. Arroyo, O. Hoffmann, L. Maboko, D. L. Birx, D. Mmbando, F. E. McCutchan and M. Hoelscher (2006). "Frequency of HIV type 1 dual infection and HIV diversity: analysis of low- and high-risk populations in Mbeya Region, Tanzania." AIDS Res Hum Retroviruses 22(7): 599-606.
14. Keele, B. F., E. E. Giorgi, J. F. Salazar-Gonzalez, J. M. Decker, K. T. Pham, M. G. Salazar, C. Sun, T. Grayson, S. Wang, H. Li, X. Wei, C. Jiang, J. L. Kirchherr, F. Gao, J. A. Anderson, L. H. Ping, R. Swanstrom, G. D. Tomaras, W. A. Blattner, P. A. Goepfert, J. M. Kilby, M. S. Saag, E. L. Delwart, M. P. Busch, M. S. Cohen, D. C. Montefiori, B. F. Haynes, B. Gaschen, G. S. Athreya, H. Y. Lee, N. Wood, C. Seoighe, A. S. Perelson, T. Bhattacharya, B. T. Korber, B. H. Hahn and G. M. Shaw (2008). "Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection." Proc Natl Acad Sci U S A 105(21): 7552-7557.
15. Kong, X., J. T. West, H. Zhang, D. M. Shea, J. M'Soka T and C. Wood (2008). "The human immunodeficiency virus type 1 envelope confers higher rates of replicative fitness to perinatally transmitted viruses than to nontransmitted viruses." J Virol 82(23): 11609-11618.
16. Lassen, K. G., M. A. Lobritz, J. R. Bailey, S. Johnston, S. Nguyen, B. Lee, T. Chou, R. F. Siliciano, M. Markowitz and E. J. Arts (2009). "Elite suppressor-derived HIV-1 envelope glycoproteins exhibit reduced entry efficiency and kinetics." PLoS Pathog 5(4): e1000377.
17. Li, M., F. Gao, J. R. Mascola, L. Stamatatos, V. R. Polonis, M. Koutsoukos, G. Voss, P. Goepfert, P. Gilbert, K. M. Greene, M. Bilska, D. L. Kothe, J. F. Salazar-Gonzalez, X. Wei, J. M. Decker, B. H. Hahn and D. C. Montefiori (2005). "Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies." J Virol 79(16): 10108-10125.
18. Marozsan, A. J., D. M. Moore, M. A. Lobritz, E. Fraundorf, A. Abraha, J. D. Reeves and E. J. Arts (2005). "Differences in the fitness of two diverse wild-type human immunodeficiency virus type 1 isolates are related to the efficiency of cell binding and entry." J Virol 79(11): 7121-7134.
19. Martinez-Picado, J., J. G. Prado, E. E. Fry, K. Pfafferott, A. Leslie, S. Chetty, C. Thobakgale, I. Honeyborne, H. Crawford, P. Matthews, T. Pillay, C. Rousseau, J. I. Mullins, C. Brander, B. D. Walker, D. I. Stuart, P. Kiepiela and P. Goulder (2006). "Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1." J Virol 80(7): 3617-3623.
20. Miura, T., Z. L. Brumme, M. A. Brockman, P. Rosato, J. Sela, C. J. Brumme, F. Pereyra, D. E. Kaufmann, A. Trocha, B. L. Block, E. S. Daar, E. Connick, H. Jessen, A. D. Kelleher, E. Rosenberg, M. Markowitz, K. Schafer, F. Vaida, A. Iwamoto, S. Little and B. D. Walker (2010). "Impaired replication capacity of acute/early viruses in persons who become HIV controllers." J Virol 84(15): 7581-7591.
21. Nofemela, A., G. Bandawe, R. Thebus, J. Marais, N. Wood, O. Hoffmann, L. Maboko, M. Hoelscher, Z. Woodman and C. Williamson (2011). "Defining the human immunodeficiency virus type 1 transmission genetic bottleneck in a region with multiple circulating subtypes and recombinant forms." Virology 415(2): 107-113.
22. Ochsenbauer, C., T. G. Edmonds, H. Ding, B. F. Keele, J. Decker, M. G. Salazar, J. F. Salazar-Gonzalez, R. Shattock, B. F. Haynes, G. M. Shaw, B. H. Hahn and J. C. Kappes (2012). "Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages." J Virol 86(5): 2715-2728.
23. Parker, Z. F., S. S. Iyer, C. B. Wilen, N. F. Parrish, K. C. Chikere, F. H. Lee, C. A. Didigu, R. Berro, P. J. Klasse, B. Lee, J. P. Moore, G. M. Shaw, B. H. Hahn and R. W. Doms (2013). "Transmitted/founder and chronic HIV-1 envelope proteins are distinguished by differential utilization of CCR5." J Virol 87(5): 2401-2411.
24. Parrish, N. F., F. Gao, H. Li, E. E. Giorgi, H. J. Barbian, E. H. Parrish, L. Zajic, S. S. Iyer, J. M. Decker, A. Kumar, B. Hora, A. Berg, F. Cai, J. Hopper, T. N. Denny, H. Ding, C. Ochsenbauer, J. C. Kappes, R. P. Galimidi, A. P. West, Jr., P. J. Bjorkman, C. B. Wilen, R. W. Doms, M. O'Brien, N. Bhardwaj, P. Borrow, B. F. Haynes, M. Muldoon, J. P. Theiler, B. Korber, G. M. Shaw and B. H. Hahn (2013). "Phenotypic properties of transmitted founder HIV-1." Proc Natl Acad Sci U S A 110(17): 6626-6633.
25. Ping, L. H., S. B. Joseph, J. A. Anderson, M. R. Abrahams, J. F. Salazar-Gonzalez, L. P. Kincer, F. K. Treurnicht, L. Arney, S. Ojeda, M. Zhang, J. Keys, E. L. Potter, H. Chu, P. Moore, M. G. Salazar, S. Iyer, C. Jabara, J. Kirchherr, C. Mapanje, N. Ngandu, C. Seoighe, I. Hoffman, F. Gao, Y. Tang, C. Labranche, B. Lee, A. Saville, M. Vermeulen, S. Fiscus, L. Morris, S. A. Karim, B. F. Haynes, G. M. Shaw, B. T. Korber, B. H. Hahn, M. S. Cohen, D. Montefiori, C. Williamson, R. Swanstrom, C. A. I. Study and H. I. V. A. V. I. C. the Center for (2013). "Comparison of viral Env proteins from acute and chronic infections with subtype C human immunodeficiency virus type 1 identifies differences in glycosylation and CCR5 utilization and suggests a new strategy for immunogen design." J Virol 87(13): 7218-7233.
26. Poncelet, P., G. Poinas, P. Corbeau, C. Devaux, N. Tubiana, N. Muloko, C. Tamalet, J. C. Chermann, F. Kourilsky and J. Sampol (1991). "Surface CD4 density remains constant on lymphocytes of HIV-infected patients in the progression of disease." Res Immunol 142(4): 291-298.
27. Prince, J. L., D. T. Claiborne, J. M. Carlson, M. Schaefer, T. Yu, S. Lahki, H. A. Prentice, L. Yue, S. A. Vishwanathan, W. Kilembe, P. Goepfert, M. A. Price, J. Gilmour, J. Mulenga, P. Farmer, C. A. Derdeyn, J. Tang, D. Heckerman, R. A. Kaslow, S. A. Allen and E. Hunter (2012). "Role of transmitted Gag CTL polymorphisms in defining replicative capacity and early HIV-1 pathogenesis." PLoS Pathog 8(11): e1003041.
28. Provine, N. M., W. B. Puryear, X. Wu, J. Overbaugh and N. L. Haigwood (2009). "The infectious molecular clone and pseudotyped virus models of human immunodeficiency virus type 1 exhibit significant differences in virion composition with only moderate differences in infectivity and inhibition sensitivity." J Virol 83(17): 9002-9007.
29. Quinones-Mateu, M. E., S. C. Ball, A. J. Marozsan, V. S. Torre, J. L. Albright, G. Vanham, G. van Der Groen, R. L. Colebunders and E. J. Arts (2000). "A dual infection/competition assay shows a correlation between ex vivo human immunodeficiency virus type 1 fitness and disease progression." J Virol 74(19): 9222-9233.
30. Rangel, H. R., J. Weber, B. Chakraborty, A. Gutierrez, M. L. Marotta, M. Mirza, P. Kiser, M. A. Martinez, J. A. Este and M. E. Quinones-Mateu (2003). "Role of the human immunodeficiency virus type 1 envelope gene in viral fitness." J Virol 77(16): 9069-9073.
31. Riedner, G., O. Hoffmann, M. Rusizoka, D. Mmbando, L. Maboko, H. Grosskurth, J. Todd, R. Hayes and M. Hoelscher (2006). "Decline in sexually transmitted infection prevalence and HIV incidence in female barworkers attending prevention and care services in Mbeya Region, Tanzania." AIDS 20(4): 609-615.
32. Salazar-Gonzalez, J. F., M. G. Salazar, B. F. Keele, G. H. Learn, E. E. Giorgi, H. Li, J. M. Decker, S. Wang, J. Baalwa, M. H. Kraus, N. F. Parrish, K. S. Shaw, M. B. Guffey, K. J. Bar, K. L. Davis, C. Ochsenbauer-Jambor, J. C. Kappes, M. S. Saag, M. S. Cohen, J. Mulenga, C. A. Derdeyn, S. Allen, E. Hunter, M. Markowitz, P. Hraber, A. S. Perelson, T. Bhattacharya, B. F. Haynes, B. T. Korber, B. H. Hahn and G. M. Shaw (2009). "Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection." J Exp Med 206(6): 1273-1289.
33. Song, H., J. W. Pavlicek, F. Cai, T. Bhattacharya, H. Li, S. S. Iyer, K. J. Bar, J. M. Decker, N. Goonetilleke, M. K. Liu, A. Berg, B. Hora, M. S. Drinker, J. Eudailey, J. Pickeral, M. A. Moody, G. Ferrari, A. McMichael, A. S. Perelson, G. M. Shaw, B. H. Hahn, B. F. Haynes and F. Gao (2012). "Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome." Retrovirology 9: 89.
34. Travers, S. A., M. J. O'Connell, G. P. McCormack and J. O. McInerney (2005). "Evidence for heterogeneous selective pressures in the evolution of the env gene in different human immunodeficiency virus type 1 subtypes." J Virol 79(3): 1836-1841.
35. van Harmelen, J., C. Williamson, B. Kim, L. Morris, J. Carr, S. S. Karim and F. McCutchan (2001). "Characterization of full-length HIV type 1 subtype C sequences from South Africa." AIDS Res Hum Retroviruses 17(16): 1527-1531.
36. Williamson, C., L. Morris, M. F. Maughan, L. H. Ping, S. A. Dryga, R. Thomas, E. A. Reap, T. Cilliers, J. van Harmelen, A. Pascual, G. Ramjee, G. Gray, R. Johnston, S. A. Karim and R. Swanstrom (2003). "Characterization and selection of HIV-1 subtype C isolates for use in vaccine development." AIDS Res Hum Retroviruses 19(2): 133-144.
37. Yue, L., K. J. Pfafferott, J. Baalwa, K. Conrod, C. C. Dong, C. Chui, R. Rong, D. T. Claiborne, J. L. Prince, J. Tang, R. M. Ribeiro, E. Cormier, B. H. Hahn, A. S. Perelson, G. M. Shaw, E. Karita, J. Gilmour, P. Goepfert, C. A. Derdeyn, S. A. Allen, P. Borrow and E. Hunter (2015). "Transmitted Virus Fitness and Host T Cell Responses Collectively Define Divergent Infection Outcomes in Two HIV-1 Recipients." PLoS Pathog 11(1): e1004565.