Abstract
Broadly neutralizing antibodies to HIV-1 usually develops in chronic infections. Here, we examined the basis of enhanced sensitivity of an env clone amplified from cross neutralizing plasma of an antiretroviral naïve chronically infected Indian patient (ID50 >600-fold higher compared to other autologous env clones). The enhanced autologous neutralization of pseudotyped viruses expressing the sensitive envelope (Env) was associated with increased sensitivity to reagents and monoclonal antibodies targeting distinct sites in Env. Chimeric viruses constructed by swapping fragments of sensitive Env into resistant Env backbone revealed that the presence of unique residues within C2V3 region of gp120 governed increased neutralization. The enhanced virus neutralization was also associated with low CD4 dependence as well as increased binding of Env trimers to IgG1b12 and CD4-IgG2 and was independent of gp120 shedding. Our data highlighted vulnerabilities in the Env obtained from cross neutralizing plasma associated with the exposure of discontinuous neutralizing epitopes and enhanced autologous neutralization. Such information may aid in Env-based vaccine immunogen design.
Highlights
The remarkable diversity and compactness of heavily glycosylated Human Immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein restricts immune evasion by neutralizing antibodies, thereby posing impediment in generating a strong and sustained neutralizing antibody response
We previously reported [23] that the plasma of an antiretroviral therapy (ART) naıve Indian patient NARI-LT5 who was chronically infected with HIV-1 for over eight years showed cross neutralization of several heterologous clade C and non-clade C including tier 2 and 3 Envs suggesting presence of broadly cross neutralizing antibodies (BCN)
Since the unique sequence of the C2V3 region was found to modulate both the neutralization sensitivity and binding of Envs to IgG1b12 and CD4-IgG2 which are the prototypic ligands that bind to CD4 binding site antibodies (CD4bs) on Env trimer, we subsequently examined the effect of this modulation on the infectivity and CD4 dependence of these Envs
Summary
The remarkable diversity and compactness of heavily glycosylated Human Immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein restricts immune evasion by neutralizing antibodies, thereby posing impediment in generating a strong and sustained neutralizing antibody response. HIV-1 is known to adopt multiple mechanisms to escape from the immune response through faster evolution of highly variable envelope protein [12,13]. These challenges have hindered the design of appropriate immunogens that would elicit broad NAbs. Recent discoveries of a number of broad and potent human neutralizing monoclonal antibodies to HIV-1 [14,15,16] from rare donors have highlighted directions in designing immunogens that would elicit such antibodies. An immunogen that can elicit the antibodies of both these specificities can mount severe pressure on the virus and help in widening the breadth of the response
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