Different resistance mutations can be detected simultaneously in the blood and the lung of HIV‐1 infected individuals on antiretroviral therapy

White, Natalie C.; Israel-Biet, Dominique; Coker, Richard; Mitchell, David M.; Weber, Jonathan; Clarke, John R.

doi:10.1002/jmv.20010

Cited by 12 publications

(10 citation statements)

References 34 publications

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“…Inflammatory cytokines are associated with increased HIV-1 replication [35], and may have contributed to the differences between viruses we amplified from the sputum and blood, as well as those with pulmonary infections in previous studies [23,24,26]. We reason that increased immune activation in cells within the respiratory tract mucosa and associated lymphoid tissue, even in the absence of respiratory symptoms, could enhance viral replication and/or the proliferation of infected cells compared to the blood.…”

Section: Discussionmentioning

confidence: 99%

“…Most of these specimens were obtained during active pulmonary disease, when increased immune activation and viral replication would be expected. High concentrations of HIV-1 in the lung compared to other organs collected during autopsy [25], and different drug-resistance mutations (assessed by consensus sequencing) in bronchoalveolar lavage compared to blood specimens collected during failing ART [26], also suggest that the lung may be a site of increased or differential HIV-1 replication.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Increased mutations in Env and Pol suggest greater HIV-1 replication in sputum-derived viruses compared with blood-derived viruses

Wagner

Tobin

McKernan

et al. 2009

Aids

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Objective Low-level HIV-1 replication may occur during antiretroviral therapy (ART) that suppresses plasma HIV-1 RNA to <50c/mL (suppressive ART). Antiretroviral drugs appear less effective in macrophages and monocytes compared to lymphocytes, both in vitro, and as implied in vivo by greater viral evolution observed during suppressive ART. Our objective was to examine sputum, which is rich in macrophages for evidence of increased HIV-1 replication compared to that in the blood during suppressive ART. Design Cross sectional study during suppressive ART. Comparison of HIV-1 DNA sequences derived from induced sputa and peripheral blood mononuclear cells (PBMC). Methods Multiple sequences encoding HIV-1 reverse transcriptase, protease, and envelope were generated using single-genome-sequencing. Reverse transcriptase and protease sequences were analyzed for genotypic drug resistance. The evolutionary distances of env sequences from the inferred most recent common ancestor of infection were calculated and CXCR4 co-receptor usage was predicted. Results 970 bidirectional sequences from 11 individuals were analyzed. HIV-1 env and pol derived from sputa had greater frequency of drug resistance mutations (P = 0.05), evolutionary divergence (P = 0.004) and tendency for CXCR4 usage (P = 0.1) compared to viruses derived from PBMC. Conclusion The greater frequency of HIV-1 drug resistance mutations and divergence of HIV-1 env in sputa- compared to PBMC-derived viruses suggests greater HIV-1 replication in the respiratory tract compared to the blood. Characterization of viral evolution over time and by cell-type could identify cells that provide a sanctuary for low-level viral replication in the respiratory tract during suppressive ART.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased mutations in Env and Pol suggest greater HIV-1 replication in sputum-derived viruses compared with blood-derived viruses

Wagner

Tobin

McKernan

et al. 2009

Aids

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“…Discordant mutation patterns in the reverse transcriptase and protease genes have been observed in HIV isolates derived from plasma and cell free bronchoalveolar lavage fluid 86. Likewise, HIV DNA recovered from PBMC and cells from bronchoalveolar lavage fluid showed discordant patterns of drug resistance mutations in some cases 86…”

Section: Tissue Compartmentalization Of Hivmentioning

confidence: 99%

“…The low level of RNA detected in alveolar macrophages also suggests the lung is of limited importance as a site of HIV replication 83,84. However, larger amounts of HIV RNA have been detected in bronchoalveolar lavage fluid 85,86. Some discordance between drug resistance mutations in the RT gene of HIV from bronchoalveolar lavage fluid and plasma has also been reported 86…”

Section: Tissue Reservoirsmentioning

confidence: 99%

HIV reservoirs in vivo and new strategies for possible eradication of HIV from the reservoir sites

Saksena

Wang²,

Zhou³

et al. 2010

HIV

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Even though the treatment of human immunodeficiency virus (HIV)-infected individuals with highly active antiretroviral therapy (HAART) provides a complete control of plasma viremia to below detectable levels (<40 copies/mL plasma), there is an unequal distribution of all antiretroviral drugs across diverse cellular and anatomic compartments in vivo. The main consequence of this is the acquisition of resistance by HIV to all known classes of currently prescribed antiretroviral drugs and the establishment of HIV reservoirs in vivo. HIV has a distinct advantage of surviving in the host via both pre-and postintegration latency. The postintegration latency is caused by inert and metabolically inactive provirus, which cannot be accessed either by the immune system or the therapeutics. This integrated provirus provides HIV with a safe haven in the host where it is incessantly challenged by its immune selection pressure and also by HAART. Thus, the provirus is one of the strategies for viral concealment in the host and the provirus can be rekindled, through unknown stimuli, to create progeny for productive infection of the host. Thus, the reservoir establishment remains the biggest impediment to HIV eradication from the host. This review provides an overview of HIV reservoir sites and discusses both the virtues and problems associated with therapies/strategies targeting these reservoir sites in vivo.

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“…Macrophages are the most common cell type in the lungs and have favorable characteristics to act as the major HIV reservoir in this compartment, which includes their resistance to apoptosis and reduced bioavailability of ARVs compared to T lymphocytes . Discordance in drug resistance patterns in the HIV reverse transcriptase and protease genes has been reported between bronchoalveolar lavage fluid and plasma . In addition, HIV evolution in the lungs was detected in 56% of individuals by comparing the C2‐V5 region of the envelope gene in sequences from paired blood and lung samples .…”

Section: Respiratory Tractmentioning

confidence: 99%

Mechanisms of HIV persistence in HIV reservoirs

Mzingwane

Tiemessen

2017

Reviews in Medical Virology

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The establishment and maintenance of HIV reservoirs that lead to persistent viremia in patients on antiretroviral drugs remains the greatest challenge of the highly active antiretroviral therapy era. Cellular reservoirs include resting memory CD4+ T lymphocytes, implicated as the major HIV reservoir, having a half-life of approximately 44 months while this is less than 6 hours for HIV in plasma. In some individuals, persistent viremia consists of invariant HIV clones not detected in circulating resting CD4+ T lymphocytes suggesting other possible sources of residual viremia. Some anatomical reservoirs that may harbor such cells include the brain and the central nervous system, the gastrointestinal tract and the gut-associated lymphoid tissue and other lymphoid organs, and the genital tract. The presence of immune cells and other HIV susceptible cells, occurring in differing compositions in anatomical reservoirs, coupled with variable and poor drug penetration that results in suboptimal drug concentrations in some sites, are all likely factors that fuel the continued low-level replication and persistent viremia during treatment. Latently, HIV-infected CD4+ T cells harboring replication-competent virus, HIV cell-to-cell spread, and HIV-infected T cell homeostatic proliferation due to chronic immune activation represent further drivers of this persistent HIV viremia during highly active antiretroviral therapy.

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Different resistance mutations can be detected simultaneously in the blood and the lung of HIV‐1 infected individuals on antiretroviral therapy

Cited by 12 publications

References 34 publications

Increased mutations in Env and Pol suggest greater HIV-1 replication in sputum-derived viruses compared with blood-derived viruses

Increased mutations in Env and Pol suggest greater HIV-1 replication in sputum-derived viruses compared with blood-derived viruses

HIV reservoirs in vivo and new strategies for possible eradication of HIV from the reservoir sites

Mechanisms of HIV persistence in HIV reservoirs

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