Human Immunodeficiency Virus Type 1 (HIV-1)Quasispecies at the Sites ofMycobacterium tuberculosisInfectionContribute to Systemic HIV-1 Heterogeneity

Abstract

We have recently reported an increased heterogeneity in the human immunodeficiency virus type 1 (HIV-1) envelope gene (env) in HIV-1-infected patients with pulmonary tuberculosis (TB) compared to patients with HIV-1 alone. This increase may be a result of dissemination of lung-derived HIV-1 isolates from sites of Mycobacterium tuberculosis infection and/or the systemic activation of the immune system in response to TB. To distinguish between these two mechanisms, blood and pleural fluid samples were obtained from HIV-1-infected patients with active pleural TB in Kampala, Uganda (CD4 cell counts of 34 to 705 cells/l, HIV-1 plasma loads of 2,400 to 280,000 RNA copies/ml, and HIV-1 pleural loads of 7,600 to 4,500,000 RNA copies/ml). The C2-C3 coding region of HIV-1 env was PCR amplified from lysed peripheral blood mononuclear cells and pleural fluid mononuclear cells and reverse transcriptase-PCR amplified from plasma and pleural fluid HIV-1 virions of eight HIV-1 patients with pleural TB. Phylogenetic and phenetic analyses revealed a compartmentalization of HIV-1 quasispecies between blood and pleural space in four of eight patients, with migration events between the compartments. There was a trend for a greater genetic heterogeneity in the pleural space, which may be the result of an M. tuberculosis-mediated increase in HIV-1 replication and/or selection pressure at the site of infection. Collectively, these findings suggest that HIV-1 quasispecies in the M. tuberculosis-infected pleural space may leak into the systemic circulation and lead to increased systemic HIV-1 heterogeneity during TB.

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

“…Our findings parallel those of Collins et al 15 that demonstrated divergent HIV evolution in pleural TB granulomas. In both instances, physical separation appears to promote viral Coreceptor usage is indicated as percentage number of sequences.…”

“…[10][11][12][13][14] Whether the same is true within TB coinfected granulomas is currently unclear and inconclusive. [15][16][17] Understanding the dynamics of viral evolution within this unique highly compartmentalized but immunologically active environment is important to virus eradication strategies. The nature of the viral variants, their response to treatment, and the mechanisms that govern their progression to sequestration may play critical roles in clinical patient management.…”

Mycobacterium tuberculosis-Induced CXCR4 and Chemokine Expression Leads to Preferential X4 HIV-1 Replication in Human Macrophages

“…We also found a putative SI phenotype in one of the three macrophage-derived HIV-1 viruses in the BAL fluid (5). The biological phenotype and coreceptor usage of HIV in the alveolar space seem to be different from those in the pleural space, where the nonsyncytium-inducing CCR5-tropic phenotype predominates (12,52,53). Taken together these data suggest that virus derived from AM during TB has an X4 phenotype.…”

“…In the CNS, syncytium-inducing (SI) X4 virus can replicate in macrophages (11). In TB, X4 virus is obtained from the lung, whereas R5 virus is found in the pleural space, suggesting compartment-specific support replication of X4 or R5 virus (5,12).…”

Side Effects of the Immune System: Lessons from Tuberculosis-Related Immune Reconstitution Inflammatory Syndrome

“…Since CD4 T cells and macrophages are major components of the granuloma and most of these T cells are likely to be activated, granulomas seem to be an ideal site for HIV replication. Also proinflammatory cytokines induced by TB-host contact seem to favor HIV replication within granulomas (10).…”