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Review
. 2021 Apr 28:12:661446.
doi: 10.3389/fmicb.2021.661446. eCollection 2021.

The Interplay of HIV and Autophagy in Early Infection

Romina Cabrera-Rodríguez  1 , Silvia Pérez-Yanes  1 , Judith Estévez-Herrera  1 , Daniel Márquez-Arce  1 , Cecilia Cabrera  2 , Lucile Espert  3 , Julià Blanco  2   4 , Agustín Valenzuela-Fernández  1
Affiliations
Review

The Interplay of HIV and Autophagy in Early Infection

Romina Cabrera-Rodríguez et al. Front Microbiol. .

Abstract

HIV/AIDS is still a global threat despite the notable efforts made by the scientific and health communities to understand viral infection, to design new drugs or to improve existing ones, as well as to develop advanced therapies and vaccine designs for functional cure and viral eradication. The identification and analysis of HIV-1 positive individuals that naturally control viral replication in the absence of antiretroviral treatment has provided clues about cellular processes that could interact with viral proteins and RNA and define subsequent viral replication and clinical progression. This is the case of autophagy, a degradative process that not only maintains cell homeostasis by recycling misfolded/old cellular elements to obtain nutrients, but is also relevant in the innate and adaptive immunity against viruses, such as HIV-1. Several studies suggest that early steps of HIV-1 infection, such as virus binding to CD4 or membrane fusion, allow the virus to modulate autophagy pathways preparing cells to be permissive for viral infection. Confirming this interplay, strategies based on autophagy modulation are able to inhibit early steps of HIV-1 infection. Moreover, autophagy dysregulation in late steps of the HIV-1 replication cycle may promote autophagic cell-death of CD4+ T cells or control of HIV-1 latency, likely contributing to disease progression and HIV persistence in infected individuals. In this scenario, understanding the molecular mechanisms underlying HIV/autophagy interplay may contribute to the development of new strategies to control HIV-1 replication. Therefore, the aim of this review is to summarize the knowledge of the interplay between autophagy and the early events of HIV-1 infection, and how autophagy modulation could impair or benefit HIV-1 infection and persistence, impacting viral pathogenesis, immune control of viral replication, and clinical progression of HIV-1 infected patients.

Keywords: Env signaling; HIV-1; autophagy; cell-death; early infection.

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Conflict of interest statement

JB is founder and shareholder of AlbaJuna Therapeutics, S.L. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
HIV-1 modulation of autophagy during early infection and viral non-productive bystander cell contact, and in persistent infected cells/tissues. Cell scheme summarizing the effect of HIV-1 on autophagy and associated factors in different HIV-1 scenarios. (A) HIV-1 Env mediates autophagy inhibition during early infection in CD4+ T cells. Autophagy associated factors affected by HIV-1 Env signaling are shown in blue boxes. (B) This scheme shows that HIV-1 Env requires active ARF6 associated autophagy factor for productive infection in CD4+ T cells. (C) This panel shows autophagy associated factors (blue boxes) that are activated during non-productive virus-bystander cell contacts. This HIV-1 Env-triggered late autophagy activation leads to CD4+ cell death. (D) This panel shows autophagy associated factors (in blue boxes) that are activated by HIV-1 infection in persistent infected cells and/or tissues. Arrow colors represent the reported positive (green) and negative (red) effects on the different steps of the viral life cycle, with dotted arrows signaling the HIV-1 activation pathway. This figure supports the information summarized in Table 1. Cell schemes were created with BioRender.com.
FIGURE 2
FIGURE 2
Effect of autophagy modulation on HIV-1 infection. Cell scheme summarizing the autophagy modulatory effect on HIV-1 viral life cycle (early steps: viral entry and infection; late steps: viral replication). (A) This panel shows that chemical inhibitors of autophagy and associated factors could activate (factors indicated in green boxes) or prevent (factors indicated in pink boxes) early HIV- 1 infection (left), or promote viral replication (right). (B) This panel shows the effect of mutants of autophagy associated factors, or specific RNAi or CRISPR/Cas editing acting on autophagy-associated genes in HIV-1 early infection or viral replication. Autophagic factors that activate HIV-1 infection or replication are indicated in green boxes, whereas factors inhibiting HIV-1 are indicated in pink boxes. Arrow colors represent the reported positive (green) and negative (red) effects on the different steps of the viral life cycle, with dotted arrows signaling the HIV-1 activation pathway. This figure supports the information summarized in Table 2. Cell schemes were created with BioRender.com.
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