HIV-1 subtype A envelope variants from early in infection have variable sensitivity to neutralization and to inhibitors of viral entry.
BACKGROUND
An effective HIV-1 vaccine or microbicide must block the transmitted virus variants that initially establish a new infection; consequently, it is critical that such viruses be isolated and characterized.


OBJECTIVE
To evaluate HIV-1 envelope variants from early in infection from individuals infected heterosexually with subtype A HIV-1 for their sensitivity to antibody-mediated neutralization and to inhibitors of viral entry.


METHODS
Full-length subtype A HIV-1 envelope clones from 28-75 days postinfection were used to generate pseudoviruses for infection studies. The susceptibility of these pseudoviruses to neutralization by autologous and heterologous plasma and by monoclonal antibodies was examined. The sensitivity of these pseudoviruses to PSC-RANTES and TAK-779, inhibitors of CCR5, and to soluble CD4 (sCD4) was also evaluated.


RESULTS
Pseudoviruses with subtype A HIV-1 envelopes from early in infection demonstrated a broad range of neutralization sensitivities to both autologous and heterologous plasma. However, neutralization by the monoclonal antibodies b12, 2G12, 4E10 and 2F5 was generally poor; notably, none of the 14 early virus variants were neutralized by 2G12 and only one was neutralized by b12. Viruses bearing these early CCR5-using envelopes were generally sensitive to the CCR5 inhibitors PSC-RANTES and TAK-779, but they demonstrated more variable sensitivity to sCD4.


CONCLUSIONS
These subtype A HIV-1 variants, representing the viruses that must be blocked by antibody-based prevention strategies, vary in their susceptibility to neutralization. A subset of these HIV-1 variants from early in infection will be useful for screening candidate vaccines and microbicides.
Blish
Catherine A
CA
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
Nedellec
Rebecca
R
Mandaliya
Kishorchandra
K
Mosier
Donald E
DE
Overbaugh
Julie
J
D000577:Amides / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000276:immunology; D018946:Chemokine CCL5 / Q000276:immunology; D005260:Female; D015488:HIV Antigens / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D019302:HIV Envelope Protein gp160 / Q000276:immunology; D023581:HIV Fusion Inhibitors / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000145:classification* / Q000276:immunology; D006801:Humans; D007630:Kenya; D009500:Neutralization Tests; D010802:Phylogeny; D000644:Quaternary Ammonium Compounds / Q000276:immunology; D019713:Receptors, CCR5 / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology*
D000577:Amides; D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D018946:Chemokine CCL5; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D023581:HIV Fusion Inhibitors; D000644:Quaternary Ammonium Compounds; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins; C119369:TAK 779