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J Virol. Jul 2007; 81(13): 7280–7285.
Published online May 2, 2007. doi:  10.1128/JVI.00406-07
PMCID: PMC1933286
A Single Amino Acid of the Human Immunodeficiency Virus Type 2 Capsid Affects Its Replication in the Presence of Cynomolgus Monkey and Human TRIM5αs[down-pointing small open triangle]
Haihan Song,1 Emi E. Nakayama,1 Masaru Yokoyama,2 Hironori Sato,2 Jay A. Levy,3 and Tatsuo Shioda1*
Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan,1 Laboratory of Viral Genomics, Center for Pathogen Genomics, National Institute of Infectious Diseases, Tokyo 208-0011, Japan,2 Cancer Research Institute, School of Medicine, University of California, San Francisco, California 941433
*Corresponding author. Mailing address: Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-8346. Fax: 81-6-6879-8347. E-mail: shioda/at/biken.osaka-u.ac.jp
Received February 26, 2007; Accepted April 23, 2007.
Human immunodeficiency virus type 2 (HIV-2) strains vary widely in their abilities to grow in Old World monkey (OWM) cells such as those of cynomolgus monkeys (CM). We evaluated eight HIV-2 isolates for their sensitivities to CM TRIM5α, an anti-HIV factor in OWM cells. We found that different HIV-2 isolates showed differences in their sensitivities to CM TRIM5α. Sequence analysis showed that TRIM5α-sensitive viruses had proline at the 120th position of the capsid protein (CA), whereas TRIM5α-resistant viruses had either alanine or glutamine. Mutagenesis studies indicated that the single amino acid at the 120th position indeed affected the sensitivity of the virus to CM TRIM5α.
Human immunodeficiency virus type 1 (HIV-1) is infectious only for humans and chimpanzees. This is due in part to TRIM5α, which blocks infection early after viral entry, before the establishment of a provirus in Old World monkey (OWM) cells. Rhesus monkey and cynomolgus monkey (CM) TRIM5αs inhibit HIV-1 but not simian immunodeficiency virus isolated from macaque (SIVmac), while African green monkey (AGM) TRIM5α prevents replication of HIV-1 and SIVmac (14, 16, 26, 34). Human (Hu) TRIM5α shows very weak antiviral activity against those viruses (30, 32, 34, 35, 38) but strong resistance against N-tropic murine leukemia virus (N-MLV) (14, 31, 37). Among several splicing variants of TRIM5, an α isoform carries the SPRY or B30.2 domain that determines virus specificity of this intracellular factor (26, 27, 30, 32, 34, 35, 38).
HIV-2, simian immunodeficiency virus isolated from sooty mangabey (SIVsmm), and SIVmac have extremely similar genomes (11). SIVmac was resistant to the restriction by rhesus monkey and CM TRIM5αs (26, 34), while HIV-2 isolates GH123 and ROD were shown to be sensitive to those TRIM5αs (26, 39). Since HIV-2 isolates varied considerably in their abilities to grow in OWM cells (3, 4, 7, 22, 23), we studied the effects of CM and Hu TRIM5αs on eight different HIV-2 isolates (UC1, UC2, UC7, UC12, UC14, 9429, 12741, and GH123) (1, 3, 5, 6, 12, 17, 21, 22, 33).
We used Sendai virus (SeV) expressing CM TRIM5α (CM-TRIM5α-SeV) (26) or Hu TRIM5α (Hu-TRIM5α-SeV). We also generated SeV expressing CM TRIM5α without the SPRY domain [CM-SPRY(−)-SeV] as a negative control. There was no variation in TRIM5α expression levels among T-cell-line Hut78 cells infected with those SeVs (data not shown).
Consistent with previous observations (26), HIV-2 isolate GH123 grew to lower titers in CM-TRIM5α-SeV-infected cells and to slightly but significantly lower titers in Hu-TRIM5α-SeV-infected cells than they did in CM-SPRY(−)-SeV-infected cells (Fig. (Fig.1).1). Of the seven newly tested isolates, only UC12 showed a pattern similar to that of GH123 (Fig. (Fig.1),1), while the other six isolates, UC1, UC14, UC2, UC7, 9429, and 12741, grew to almost the same titers in CM-TRIM5α-SeV-, Hu-TRIM5α-SeV-, and CM-SPRY(−)-SeV-infected cells (Fig. (Fig.1).1). These results indicated that HIV-2 isolates GH123 and UC12 are sensitive to CM TRIM5α and moderately sensitive to Hu TRIM5α, while the isolates UC1, UC14, UC2, UC7, 9429, and 12741 are resistant to CM and Hu TRIM5αs.
FIG. 1.
FIG. 1.
Hut78 cells (105) were infected with CM-TRIM5α-SeV (open circles), Hu-TRIM5α-SeV (filled triangles), or CM-SPRY(−)-SeV (open squares) at a multiplicity of infection of 10 PFU. The CM-SPRY(−)-SeV domain was generated by (more ...)
It has been suggested that viral capsid protein (CA) was the determinant of TRIM5α restriction (13, 28, 29). We therefore determined the nucleotide sequences of PCR-amplified DNA fragments corresponding to proviral DNA encoding the CAs of the HIV-2 isolates. Figure Figure2A2A shows the deduced amino acid sequences of the HIV-2 CAs. TRIM5α-sensitive GH123 and UC12 had proline at the 120th (GH123) or corresponding 119th (UC12) position, while the other six TRIM5α-resistant isolates showed alanine (UC1 and UC14) or glutamine (UC2, UC7, 9429, and 12741) at the corresponding 119th position. Except for this substitution, there was no substitution observed commonly and specifically for GH123 and UC12.
FIG. 2.
FIG. 2.
(A) Alignments of amino acid sequences of CAs of eight HIV-2 isolates. “/S” after the names of isolates represents sensitivity to CM and Hu TRIM5α, and “/R” indicates resistance to CM and Hu TRIM5α. A dash (more ...)
To determine whether the single amino acid at the 119th or 120th position of the HIV-2 CA affects the virus's susceptibility to CM and Hu TRIM5α, we constructed two mutant GH123 viruses carrying either alanine (GH123/A) or glutamine (GH123/Q) at the 120th position (Fig. (Fig.3A).3A). As shown in Fig. Fig.3B,3B, all three viruses grew substantially and to similar titers in CM-SPRY(−)-SeV-infected MT4 cells. In CM-TRIM5α-SeV-infected cells, both GH123/A and GH123/Q grew to titers more than 250 times higher than those of the wild-type GH123. In the Hu-TRIM5α-SeV-infected cells, both mutant viruses grew to titers approximately fourfold higher than those of the wild type (Fig. (Fig.3B).3B). In contrast, replication of the three viruses could not be detected in the AGM-TRIM5α-SeV-infected cells (Fig. (Fig.3B).3B). Unlike CM TRIM5α, AGM TRIM5α possessed a potent antiviral activity against SIVmac as well as HIV-1 and HIV-2 (26, 27). These results indicate that the single amino acid at the 120th position of the GH123 CA indeed affects susceptibility to the restriction of virus replication by CM TRIM5α.
FIG. 3.
FIG. 3.
(A) Mutant GH123/A and GH123/Q viruses generated by changing a single amino acid of proline to alanine or glutamine and mutant SIVmac239/P virus generated by changing a single amino acid of glutamine to proline by site-directed mutagenesis. Dashes indicate (more ...)
There is more than 87% amino acid identity in CA between HIV-2 GH123 and SIVmac239. SIVmac239 is resistant to CM TRIM5α (26) and contains glutamine at the 118th position, which corresponds to the 120th position of the GH123 CA. To determine whether this particular amino acid also affects the resistance of SIVmac239 to CM TRIM5α, we constructed a mutant SIVmav239 carrying a proline at the 118th position (SIVmac239/P) (Fig. (Fig.3A).3A). As shown in Fig. Fig.3C,3C, both wild-type and mutant SIVmac239 grew substantially and to similar titers in the CM-SPRY(−)-SeV-infected MT4 cells. In CM-TRIM5α-SeV-infected cells, the mutant SIVmac239 grew to titers that were approximately 10 times lower than those of the wild type. The glutamine-to-proline mutation also caused an approximately eightfold decrease in the virus titer in Hu-TRIM5α-SeV-infected cells (Fig. (Fig.3C).3C). In contrast, neither virus grew in AGM-TRIM5α-SeV-infected cells (Fig. (Fig.3C).3C). These results indicate that the glutamine at the 118th position of the SIVmac239 CA also affects resistance to the CM and Hu TRIM5αs.
Nineteen HIV-2 and 20 SIVsmm or SIVmac CA sequences were listed in the Los Alamos sequence database (Fig. (Fig.2B).2B). All SIV isolates except for SMM-SL92B carried glutamine at the position corresponding to the 120th position of GH123 (Fig. (Fig.2B).2B). SMM-SL92B, which carries alanine, was most distantly related to all the other HIV-2 and SIV isolates from the phylogenetic analysis (data not shown). These results suggest that all SIV isolates are resistant to CM and Hu TRIM5αs. In contrast, HIV-2 group A isolates showed a mixture of proline, alanine, and glutamine and HIV-2 group B isolates had a mixture of proline and alanine in the CA (Fig. (Fig.2B).2B). Other HIV-2 isolates also carried proline and glutamine, with H2AB-7312A, which had glycine, being the only exception (Fig. (Fig.2B).2B). These results suggest that different HIV-2 isolates have diverse susceptibilities to CM and Hu TRIM5αs. It is likely that glutamine-to-alanine or glutamine-to-proline substitutions occurred after the proposed zoonotic transfer of virus from monkeys to humans (11).
To obtain structural insight into the mechanisms by which this amino acid change in the CA alters viral susceptibility to restriction by TRIM5α, three-dimensional (3-D) models of HIV-2 CAs were constructed with the homology-modeling technique based on the crystal structure of the HIV-1 CA N-terminal domain (15). These models consist of those with proline (GH123, UC12), alanine (UC1, UC14, GH123/A), and glutamine (UC2, UC7, 9429, 12741, GH123/Q) at the 120th position. The thermodynamically optimized 3-D structures showed that the HIV-2 CA N-terminal domains consist of a packed core structure from which seven α-helices and three loops protrude, which is basically the same conformation as that of their HIV-1 counterparts (15) (Fig. (Fig.44).
FIG. 4.
FIG. 4.
Structural model of the N-terminal halves of HIV-2 CAs. The 3-D models of 10 HIV-2 CAs were constructed with the homology-modeling technique using “MOE-Align” and “MOE-Homology” in the Molecular Operating Environment (MOE) (more ...)
The 120th amino acid that affects the viral susceptibility to TRIM5α restriction is located in the loop between helices 6 and 7 (L6/7) (Fig. (Fig.4,4, labeled Q, A, P). Especially worth noting is that the amino acid substitution at the 120th position is predicted to induce marked changes in the configuration of L6/7. The loop with the TRIM5α-sensitive proline (GH123 and UC12, Fig. Fig.4,4, labeled P) is positioned most closely to the loop between helices 4 and 5 (L4/5). We obtained results the same as those described above when we constructed HIV-2 CA models based on the HIV-1 CA structure in solution (data not shown) (8). In HIV-1, L4/5 interacts directly with cyclophilin A (15, 24, 36). It is possible that TRIM5α recognizes the particular structure formed by two closely aligned L4/5 and L6/7 with proline.
Previously, a single amino acid substitution at the 110th position of N-MLV CA was shown to determine viral susceptibility to Fv1 (20), another type of restriction factor in mice (2), as well as to Hu TRIM5α (14, 31, 37). The fact that the amino acids at analogous positions of both N-MLV and HIV-2 CAs (25, 36) affected sensitivity to Hu and CM TRIM5αs, respectively, suggested that N-MLV and HIV-2 are recognized by TRIM5α in a similar manner. It would be interesting to investigate whether the 120th position of HIV-2 CA affects its sensitivity to TRIM5α of other OWM cells.
Human TRIM5α has no or very little effect on HIV-1 or SIVmac infection (30, 32, 34, 35, 38). Unlike HIV-1 (Fig. (Fig.3D),3D), HIV-2 isolates sensitive to CM TRIM5α were slightly more sensitive to Hu TRIM5α than those resistant to CM TRIM5α (Fig. (Fig.11 and and3B).3B). As shown in Fig. Fig.4,4, half of the HIV-2 isolates in the database carried proline, which would be sensitive to Hu TRIM5α. This finding may be one of the reasons why HIV-2 is less pathogenic than HIV-1 (9). Since certain HIV-2 patients with high plasma HIV-2 loads developed AIDS as rapidly as HIV-1 patients (10), examining the effect of sensitivity to Hu TRIM5α of HIV-2 strains in infected individuals on the rate of disease progression merits attention.
Acknowledgments
We thank J. Sakuragi and S. Sakuragi for helpful discussions and S. Bandou and N. Teramoto for assistance.
This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology and the Ministry of Health, Labor and Welfare, Japan.
Footnotes
[down-pointing small open triangle]Published ahead of print on 2 May 2007.
1. Barnett, S. W., K. K. Murthy, B. G. Herndier, and J. A. Levy. 1994. An AIDS-like condition induced in baboons by HIV-2. Science 266:642-646. [PubMed]
2. Best, S., P. Le Tissier, G. Towers, and J. P. Stoye. 1996. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 382:826-829. [PubMed]
3. Castro, B. A., S. W. Barnett, L. A. Evans, J. Moreau, K. Odehouri, and J. A. Levy. 1990. Biologic heterogeneity of human immunodeficiency virus type 2 (HIV-2) strains. Virology 178:527-534. [PubMed]
4. Castro, B. A., M. Nepomuceno, N. W. Lerche, J. W. Eichberg, and J. A. Levy. 1991. Persistent infection of baboons and rhesus monkeys with different strains of HIV-2. Virology 184:219-226. [PubMed]
5. Evans, L. A., J. Moreau, K. Odehouri, H. Legg, A. Barboza, C. Cheng-Mayer, and J. A. Levy. 1988. Characterization of a noncytopathic HIV-2 strain with unusual effects on CD4 expression. Science 240:1522-1525. [PubMed]
6. Evans, L. A., J. Moreau, K. Odehouri, D. Seto, G. Thomson-Honnebier, H. Legg, A. Barboza, C. Cheng-Mayer, and J. A. Levy. 1988. Simultaneous isolation of HIV-1 and HIV-2 from an AIDS patient. Lancet ii:1389-1391.
7. Fujita, M., A. Yoshida, A. Sakurai, J. Tatsuki, F. Ueno, H. Akari, and A. Adachi. 2003. Susceptibility of HVS-immortalized lymphocytic HSC-F cells to various strains and mutants of HIV/SIV. Int. J. Mol. Med. 11:641-644. [PubMed]
8. Gitti, R. K., B. M. Lee, J. Walker, M. F. Summers, S. Yoo, and W. I. Sundquist. 1996. Structure of the amino-terminal core domain of the HIV-1 capsid protein. Science 273:231-235. [PubMed]
9. Gottlieb, G. S., S. E. Hawes, H. D. Agne, J. E. Stern, C. W. Critchlow, N. B. Kiviat, and P. S. Sow. 2006. Lower levels of HIV RNA in semen in HIV-2 compared with HIV-1 infection: implications for differences in transmission. AIDS 20:895-900. [PubMed]
10. Gottlieb, G. S., P. S. Sow, S. E. Hawes, I. Ndoye, M. Redman, A. M. Coll-Seck, M. A. Faye-Niang, A. Diop, J. M. Kuypers, C. W. Critchlow, R. Respess, J. I. Mullins, and N. B. Kiviat. 2002. Equal plasma viral loads predict a similar rate of CD4+ T cell decline in human immunodeficiency virus (HIV) type 1- and HIV-2-infected individuals from Senegal, West Africa. J. Infect. Dis. 185:905-914. [PubMed]
11. Hahn, B. H., G. M. Shaw, K. M. De Cock, and P. M. Sharp. 2000. AIDS as a zoonosis: scientific and public health implications. Science 287:607-614. [PubMed]
12. Hasegawa, A., H. Tsujimoto, N. Maki, K. Ishikawa, T. Miura, M. Fukasawa, K. Miki, and M. Hayami. 1989. Genomic divergence of HIV-2 from Ghana. AIDS Res. Hum. Retrovir. 5:593-604. [PubMed]
13. Hatziioannou, T., S. Cowan, U. K. Von Schwedler, W. I. Sundquist, and P. D. Bieniasz. 2004. Species-specific tropism determinants in the human immunodeficiency virus type 1 capsid. J. Virol. 78:6005-6012. [PMC free article] [PubMed]
14. Hatziioannou, T., D. Perez-Caballero, A. Yang, S. Cowan, and P. D. Bieniasz. 2004. Retrovirus resistance factors Ref1 and Lv1 are species-specific variants of TRIM5alpha. Proc. Natl. Acad. Sci. USA 101:10774-10779. [PubMed]
15. Howard, B. R., F. F. Vajdos, S. Li, W. I. Sundquist, and C. P. Hill. 2003. Structural insights into the catalytic mechanism of cyclophilin A. Nat. Struct. Biol. 10:475-481. [PubMed]
16. Keckesova, Z., L. M. Ylinen, and G. J. Towers. 2004. The human and African green monkey TRIM5alpha genes encode Ref1 and Lv1 retroviral restriction factor activities. Proc. Natl. Acad. Sci. USA 101:10780-10785. [PubMed]
17. Kestler, H., T. Kodama, D. Ringler, M. Marthas, N. Pedersen, A. Lackner, D. Regier, P. Sehgal, M. Daniel, N. King, et al. 1990. Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus. Science 248:1109-1112. [PubMed]
18. Kinomoto, M., R. Appiah-Opong, J. A. Brandful, M. Yokoyama, N. Nii-Trebi, E. Ugly-Kwame, H. Sato, D. Ofori-Adjei, T. Kurata, F. Barre-Sinoussi, T. Sata, and K. Tokunaga. 2005. HIV-1 proteases from drug-naive West African patients are differentially less susceptible to protease inhibitors. Clin. Infect. Dis. 41:243-251. [PubMed]
19. Kinomoto, M., M. Yokoyama, H. Sato, A. Kojima, T. Kurata, K. Ikuta, T. Sata, and K. Tokunaga. 2005. Amino acid 36 in the human immunodeficiency virus type 1 gp41 ectodomain controls fusogenic activity: implications for the molecular mechanism of viral escape from a fusion inhibitor. J. Virol. 79:5996-6004. [PMC free article] [PubMed]
20. Kozak, C. A., and A. Chakraborti. 1996. Single amino acid changes in the murine leukemia virus capsid protein gene define the target of Fv1 resistance. Virology 225:300-305. [PubMed]
21. Locher, C. P., S. W. Barnett, B. G. Herndier, D. J. Blackbourn, G. Reyes-Teran, K. K. Murthy, K. M. Brasky, G. B. Hubbard, T. A. Reinhart, A. T. Haase, and J. A. Levy. 1998. Human immunodeficiency virus-2 infection in baboons is an animal model for human immunodeficiency virus pathogenesis in humans. Arch. Pathol. Lab. Med. 122:523-533. [PubMed]
22. Locher, C. P., D. J. Blackbourn, B. G. Herndier, G. Reyes-Teran, S. W. Barnett, K. K. Murthy, and J. A. Levy. 1998. Transient virus infection and pathogenesis of a new HIV type 2 isolate, UC12, in baboons. AIDS Res. Hum. Retrovir. 14:79-82. [PubMed]
23. Locher, C. P., S. A. Witt, B. G. Herndier, N. W. Abbey, K. Tenner-Racz, P. Racz, N. B. Kiviat, K. K. Murthy, K. Brasky, M. Leland, and J. A. Levy. 2003. Increased virus replication and virulence after serial passage of human immunodeficiency virus type 2 in baboons. J. Virol. 77:77-83. [PMC free article] [PubMed]
24. Luban, J., K. L. Bossolt, E. K. Franke, G. V. Kalpana, and S. P. Goff. 1993. Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73:1067-1078. [PubMed]
25. Mortuza, G. B., L. F. Haire, A. Stevens, S. J. Smerdon, J. P. Stoye, and I. A. Taylor. 2004. High-resolution structure of a retroviral capsid hexameric amino-terminal domain. Nature 431:481-485. [PubMed]
26. Nakayama, E. E., H. Miyoshi, Y. Nagai, and T. Shioda. 2005. A specific region of 37 amino acid residues in the SPRY (B30.2) domain of African green monkey TRIM5alpha determines species-specific restriction of simian immunodeficiency virus SIVmac infection. J. Virol. 79:8870-8877. [PMC free article] [PubMed]
27. Ohkura, S., M. W. Yap, T. Sheldon, and J. P. Stoye. 2006. All three variable regions of the TRIM5alpha B30.2 domain can contribute to the specificity of retrovirus restriction. J. Virol. 80:8554-8565. [PMC free article] [PubMed]
28. Owens, C. M., B. Song, M. J. Perron, P. C. Yang, M. Stremlau, and J. Sodroski. 2004. Binding and susceptibility to postentry restriction factors in monkey cells are specified by distinct regions of the human immunodeficiency virus type 1 capsid. J. Virol. 78:5423-5437. [PMC free article] [PubMed]
29. Owens, C. M., P. C. Yang, H. Gottlinger, and J. Sodroski. 2003. Human and simian immunodeficiency virus capsid proteins are major viral determinants of early, postentry replication blocks in simian cells. J. Virol. 77:726-731. [PMC free article] [PubMed]
30. Perez-Caballero, D., T. Hatziioannou, A. Yang, S. Cowan, and P. D. Bieniasz. 2005. Human tripartite motif 5α domains responsible for retrovirus restriction activity and specificity. J. Virol. 79:8969-8978. [PMC free article] [PubMed]
31. Perron, M. J., M. Stremlau, B. Song, W. Ulm, R. C. Mulligan, and J. Sodroski. 2004. TRIM5alpha mediates the postentry block to N-tropic murine leukemia viruses in human cells. Proc. Natl. Acad. Sci. USA 101:11827-11832. [PubMed]
32. Sawyer, S. L., L. I. Wu, M. Emerman, and H. S. Malik. 2005. Positive selection of primate TRIM5alpha identifies a critical species-specific retroviral restriction domain. Proc. Natl. Acad. Sci. USA 102:2832-2837. [PubMed]
33. Shibata, R., T. Miura, M. Hayami, K. Ogawa, H. Sakai, T. Kiyomasu, A. Ishimoto, and A. Adachi. 1990. Mutational analysis of the human immunodeficiency virus type 2 (HIV-2) genome in relation to HIV-1 and simian immunodeficiency virus SIV (AGM). J. Virol. 64:742-747. [PMC free article] [PubMed]
34. Stremlau, M., C. M. Owens, M. J. Perron, M. Kiessling, P. Autissier, and J. Sodroski. 2004. The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 427:848-853. [PubMed]
35. Stremlau, M., M. Perron, S. Welikala, and J. Sodroski. 2005. Species-specific variation in the B30.2(SPRY) domain of TRIM5α determines the potency of human immunodeficiency virus restriction. J. Virol. 79:3139-3145. [PMC free article] [PubMed]
36. Towers, G. J., T. Hatziioannou, S. Cowan, S. P. Goff, J. Luban, and P. D. Bieniasz. 2003. Cyclophilin A modulates the sensitivity of HIV-1 to host restriction factors. Nat. Med. 9:1138-1143. [PubMed]
37. Yap, M. W., S. Nisole, C. Lynch, and J. P. Stoye. 2004. Trim5alpha protein restricts both HIV-1 and murine leukemia virus. Proc. Natl. Acad. Sci. USA 101:10786-10791. [PubMed]
38. Yap, M. W., S. Nisole, and J. P. Stoye. 2005. A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction. Curr. Biol. 15:73-78. [PubMed]
39. Ylinen, L. M., Z. Keckesova, S. J. Wilson, S. Ranasinghe, and G. J. Towers. 2005. Differential restriction of human immunodeficiency virus type 2 and simian immunodeficiency virus SIVmac by TRIM5α alleles. J. Virol. 79:11580-11587. [PMC free article] [PubMed]
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