Human immunodeficiency virus type 1 (HIV-1) resistance to broadly neutralizing antibodies such as b12, which targets the highly conserved CD4-binding site, raises a significant hurdle for the development of a neutralizing antibody-based vaccine. Here, 15 individuals were studied of whom seven developed b12-resistant viruses late in infection. The study investigated whether immune pressure may be involved in the selection of these viruses in vivo. Although four out of seven patients showed HIV-1-specific broadly neutralizing activity in serum, none of these patients had CD4-binding site-directed antibodies, indicating that strong humoral immunity is not a prerequisite for the outgrowth of b12-resistant viruses. In virus variants from one patient, who showed extremely weak heterologous and autologous neutralizing activity in serum, mutations were identified in the envelope that coincided with changes in b12 neutralization sensitivity. Lack of cytotoxic T-cell activity against epitopes with and without these mutations excluded a role for host cellular immunity in the selection of b12-resistant mutant viruses in this patient. However, b12 resistance correlated well with increased virus replication kinetics, indicating that selection for enhanced infectivity, possibly driven by the low availability of target cells in the later stages of disease, may coincide with increased resistance to CD4-binding site-directed agents, such as b12. These results showed that b12-resistant HIV-1 variants can emerge during the course of natural infection in the absence of both humoral and cellular immune pressure, suggestive of other mechanisms playing a role in the selective outgrowth of b12-resistant viruses.
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