The Mtb-HIV syndemic interaction: why treating M. tuberculosis infection may be crucial for HIV-1 eradication

Abstract

Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis (Mtb)-coinfected individuals indicates the important interaction between these syndemic pathogens. The immunological interaction between HIV-1 and Mtb has been largely defined by how the virus exacerbates tuberculosis disease pathogenesis. Understanding of the mechanisms by which pre-existing or subsequent Mtb infection may favor the replication, persistence and progression of HIV, is less characterized. We present a rationale for the critical consideration of 'latent' Mtb infection in HIV-1 prevention and cure strategies. In support of this position, we review evidence of the effect of Mtb infection on HIV-1 acquisition, replication and persistence. We propose that 'latent' Mtb infection may have considerable impact on HIV-1 pathogenesis and the continuing HIV-1 epidemic in sub-Saharan Africa.

Keywords: AIDS; HIV-1 cure; granuloma; immune activation; latency; transmission; tuberculosis; viral expansion; viral reservoir.

Figure 1.. Epidemiological relationship between HIV-1 prevalence and tuberculosis incidence and infection from 1990 to 2017.

(A) Prevalence of HIV-1 in adults aged 15–49, from 1990 to 2016. (B) Change in HIV-1 prevalence in adults aged 15–49 from 2000 to 2017 (countries in dark gray were not included in the analysis, grid cells with fewer than ten people per 1 × 1 km and classified as barren or sparsely vegetated, are colored light gray). (C) Estimated numbers of HIV-TB cases per 100,000 population (all ages) in 2000. (D) Age-standardized TB cases (excluding HIV) per 100,000 population (all ages) in 2016. (E) Prevalence of latent Mtb and Mtb-HIV-1 infection, TB and TB-HIV-1 disease, proportion of smear positivity attributed to TB or TB-HIV-1 and the proportion of TB (left Y-axis) and TB-HIV-1 (right Y-axis) cases smear positive in 2000, prior to HIV-1 expansion. (F) Proportion of Mtb lineages represented across African countries in pie charts. Euro-American Lineage 4 LAM strain (brown) is found most commonly in southern African countries, including those with the greatest increase in HIV-1 prevalence between 2000–2017 (B): MOZ and ZAF country codes (www.worldatlas.com/aatlas/ctycodes.htm). (A) Source: UNAIDS World Bank, OurWorldInData.org/hiv-aids/ [15,16]. (B) Reproduced with permission from [9]. (C) Reproduced with permission from [17] © American Medical Association (2003). All rights reserved. (D) Reproduced with permission from [10]. (E) Tabulated data extracted from [17] are replotted. Reproduced with permission from [17] © American Medical Association (2003). All rights reserved. (F) Reproduced with permission from [18]. LAM: Latin American Mediterranean; MOZ: Mozambique; Mtb: Mycobacterium tuberculosis; TB: Tuberculosis; ZAF: South Africa.

Figure 2.. Representation of the proposed impact of Mycobacterium tuberculosis coinfection (solid lines) on the life-course progression of HIV-1 infection (dotted lines).

A higher starting immune activation state during Mtb infection may lead to a higher peak in viral RNA (red) and infected cells with integrated viral DNA (blue) during the first few months of acute infection. As HIV-1 infection progresses over years, higher immune activation (green) persists and may result in a higher viral set point threshold and expansion of HIV-1 reservoirs cells containing HIV-1 DNA. With increased HIV-1 replication at tissue sites of Mtb infection and due to a higher proinflammatory environment and cellular activation, HIV-1 will progress faster into AIDS (red) and potential TB disease. TB will coincide with a secondary viremia peak and further expansion of infected cells with integrated DNA. Following ART initiation, a larger pool of reservoir cells harboring HIV-1 and higher immune activation status has the potential to result in more frequent blips in viremia above the level of clinical detection (thin line), following viral suppression and tissue-specific HIV-1 reservoirs persisting with cell-to-cell spread, rather than a slow reduction in cells harboring integrated viral DNA. ART: Antiretroviral therapy; Mtb: Mycobacterium tuberculosis; TB: Tuberculosis.

Figure 3.. HIV-1 lifecycle and points where Mycobacterium tuberculosis coinfection may influence this lifecycle.

(1) Viral attachment requires high affinity binding of the HIV-1 Envelope Gp120 to the host cell CD4 receptor. (2) HIV-1 interacts with either coreceptor CCR5 or CXCR4, forming a heterodimer with CD4, facilitating viral entry. (A) High levels of CCR5/CXCR4 coreceptors correlate with TB disease and activation markers CD38 and HLA-DR. (3) The Envelope Gp41 subunit protein then facilitates viral fusion and injection into the target cell membrane. (4 & 5) The viral enzyme Reverse Transcriptase converts RNA to cDNA and ultimately double-stranded DNA is produced, which is translocated to the nucleus, where the virally encoded integrase facilitates viral DNA integration into the host genome. (6 & 7) Once integrated, the virus utilizes host cellular machinery and energy to transcribe viral mRNA for packaging into new viral particles and for viral protein production. (B) HIV-1 replication may be enhanced by the proinflammatory environment created by Mtb infection or Mtb product (e.g., secreted CFP-10 or cell wall LAM) triggering of TLRs. Proinflammatory cytokines such as TNF, IL-6 and IL-1β induce transcription factors (NF-κB, AP-1, NFAT5, C/EBP), which readily bind to the viral LTR, and upregulate the transcriptional capacity of the virus. (8) The viral protease enzyme cleaves polypeptides needed for new virion assembly, which bud off the cell membrane through exosome transport. (C) Mtb may promote the establishment of a larger pool of cell-free viral particles and increase recruitment and activation of infection-susceptible cells through increased chemokine production, such as CXCL10, CXCL8 and CCL2 and proinflammatory cytokine secretion. LAM: Lipoarabinomannan; LTR: Long terminal repeat; Mtb: Mycobacterium tuberculosis; TB: Tuberculosis; TLR: Toll-like receptor.