Subtype-specific conservation of isoleucine 309 in the envelope V3 domain is linked to immune evasion in subtype C HIV-1 infection.
The V3 region of the HIV-1 envelope (Env) glycoprotein gp120 is a key functional domain yet it exhibits distinct mutational patterns across subtypes. Here an invariant residue (Ile 309) was replaced with Leu in 7 subtype C patient-derived Envs from recent infection and 4 related neutralizing antibody escape variants that emerged later. For these 11 Envs, I309L did not alter replication in primary CD4 T cells; however, replication in monocyte-derived macrophages was enhanced. Infection of cell lines with low CD4 or CCR5 revealed that I309L enhanced utilization of CD4 but did not affect the ability to use CCR5. This CD4-enhanced phenotype tracked with sensitivity to sCD4, indicating increased exposure of the CD4 binding site. The results suggest that Ile 309 preserves a V3-mediated masking function that occludes the CD4 binding site. The findings point to an immune evasion strategy in subtype C Env to protect this vulnerable immune target.
Lynch
Rebecca M
RM
Immunology and Molecular Pathogenesis Program, Emory University, Atlanta, GA 30329, USA.
Rong
Rong
R
Li
Bing
B
Shen
Tongye
T
Honnen
William
W
Mulenga
Joseph
J
Allen
Susan
S
Pinter
Abraham
A
Gnanakaran
S
S
Derdeyn
Cynthia A
CA
D019943:Amino Acid Substitution / Q000235:genetics; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D017124:Conserved Sequence; D005260:Female; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D057131:Immune Evasion; D007532:Isoleucine / Q000235:genetics*; D008264:Macrophages / Q000821:virology; D008297:Male; D016297:Mutagenesis, Site-Directed; D019713:Receptors, CCR5 / Q000378:metabolism; D015728:Receptors, HIV / Q000378:metabolism; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology; D014779:Virus Replication
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; D015728:Receptors, HIV; D037521:Virulence Factors; C514793:gp120 protein, Human immunodeficiency virus 1; D007532:Isoleucine