Abstract
BackgroundSeveral subtypes of HIV-1 circulate in infected people worldwide, including subtype B in the United States and subtype C in Africa and India. To understand the biological properties of HIV-1 subtype C, including cellular tropism, virus entry, replication efficiency and cytopathic effects, we reciprocally inserted our previously characterized envelope V3–V5 regions derived from 9 subtype C infected patients from India into a subtype B molecular clone, pNL4-3. Equal amounts of the chimeric viruses were used to infect T-lymphocyte cell lines (A3.01 and MT-2), coreceptor cell lines (U373-MAGI-CCR5/CXCR4), primary blood T-lymphocytes (PBL) and monocyte-derived macrophages (MDM).ResultsWe found that subtype C envelope V3–V5 region chimeras failed to replicate in T-lymphocyte cell lines but replicated in PBL and MDM. In addition, these chimeras were able to infect U373MAGI-CD4+-CCR5+ but not U373MAGI-CD4+-CXCR4+ cell line, suggesting CCR5 coreceptor utilization and R5 phenotypes. These subtype C chimeras were unable to induce syncytia in MT-2 cells, indicative of non-syncytium inducing (NSI) phenotypes. More importantly, the subtype C envelope chimeras replicated at higher levels in PBL and MDM compared with subtype B chimeras and isolates. Furthermore, the higher levels subtype C chimeras replication in PBL and MDM correlated with increased virus entry in U373MAGI-CD4+-CCR5+.ConclusionTaken together, these results suggest that the envelope V3 to V5 regions of subtype C contributed to higher levels of HIV-1 replication compared with subtype B chimeras, which may contribute to higher viral loads and faster disease progression in subtype C infected individuals than other subtypes as well as rapid HIV-1 subtype C spread in India.
Highlights
The steepest increase in new cases of human immunodeficiency virus type 1 (HIV-1) infection has taken place in South America [1] and South/Southeast Asia [2], of which India is experiencing a rapid and extensive spread of infection
We show that the envelope V3–V5 regions of HIV-1 subtype C changed the tropism of HIV-1 NL4-3 from X4 to R5 and contributed to the increased virus entry and replication efficiency in primary blood Tlymphocytes (PBL) and monocyte-derived macrophages (MDM) compared with subtype B viruses
Characterization and comparison of subtype C envelope V3–V5 chimeras' sequences with known isolates We confirmed the reciprocal insertion of the sixteen envelope V3–V5 region sequences (Fig. 1) from nine subtype C infected patients' isolates from India (Table 1) that were sequenced before [5] into pNL4-3 by nucleotide sequencing
Summary
The steepest increase in new cases of human immunodeficiency virus type 1 (HIV-1) infection has taken place in South America [1] and South/Southeast Asia [2], of which India is experiencing a rapid and extensive spread of infection. Several studies have shown that a reciprocal transfer of an HIV-1 R5 clones' V3 region into an X4 molecular clone changed its tropism to allow infection and replication in macrophages [10,19,23,28,29,30]. Most of the data on viral infectivity, coreceptor utilization, replication efficiency and cytopathic effects have been obtained from HIV-1 subtype B, and very limited information is available on subtype C viruses, especially those from India. To understand the biological properties of HIV-1 subtype C, including cellular tropism, virus entry, replication efficiency and cytopathic effects, we reciprocally inserted our previously characterized envelope V3–V5 regions derived from 9 subtype C infected patients from India into a subtype B molecular clone, pNL4-3. Equal amounts of the chimeric viruses were used to infect T-lymphocyte cell lines (A3.01 and MT-2), coreceptor cell lines (U373-MAGI-CCR5/CXCR4), primary blood T-lymphocytes (PBL) and monocyte-derived macrophages (MDM)
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