Cellular specificity of HIV-1 replication can be controlled by LTR sequences

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Retroviral tropism is determined by envelope sequences for entry and LTR sequences for cell-specific expression.
• Human immunodeficiency virus-1 (HIV-1) tropism is primarily linked to variable envelope sequences.
• While T cell and macrophage-specific transcription factor motifs exist in the HIV-1 LTR, core enhancer elements function broadly, leading to the conclusion that LTRs are not primary tropism determinants.

Purpose of the Study:

• To investigate whether HIV-1 LTR sequences can impart cellular specificity to viral replication.
• To determine if modifying core enhancer elements can direct HIV-1 expression in a cell-specific manner.

Main Methods:

• The enhancer/promoter proximal region of the HIV-1 LTR was replaced with myeloid-specific expression motifs.
• Equine infectious anemia virus (EIAV) enhancer sequences were used to confer macrophage-specific expression.
• Chimeric LTRs were constructed and inserted into a dual-tropic HIV-1 infectious molecular clone for infectivity studies.

Main Results:

• Substitution with the EIAV enhancer region resulted in macrophage-specific expression, responsive to HIV Tat.
• Addition of a methylation-dependent binding site (MDBP) and Sp1 motif enhanced expression without changing cellular specificity.
• Chimeric LTRs directed HIV-1 replication and infectious virion production in macrophages but not in primary T cells or T cell lines.

Conclusions:

• Cellular tropism of HIV-1 can be modulated at the level of viral transcription via LTR modifications.
• HIV-1 LTR sequences, not just envelope proteins, can be engineered to control cell-specific viral replication.
• This study demonstrates a mechanism for imparting macrophage tropism to HIV-1 through transcriptional control.