HIV Pathogenesis in the Human Female Reproductive Tract

Rodriguez-García, Marta; Connors, Kaleigh; Ghosh, Mimi

doi:10.1007/s11904-021-00546-1

Cited by 15 publications

(13 citation statements)

References 239 publications

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“…Data also indicate that the vaginal microbiome changes after menopause, with a decreased presence of Lactobacillus species compared to premenopausal women [ 22 , 23 , 24 ]. This fact, together with changes in immune cell responses, the pro-inflammatory environment, and a reduction of protective mediators in the female reproductive tract (FRT), may increase the risk of HIV acquisition in postmenopausal women [ 7 , 23 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Short-Chain Fatty Acids Impair Neutrophil Antiviral Function in an Age-Dependent Manner

Carrillo‐Salinas

Parthasarathy

Lara

et al. 2022

Cells

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Half of the people living with HIV are women. Younger women remain disproportionally affected in endemic areas, but infection rates in older women are rising worldwide. The vaginal microbiome influences genital inflammation and HIV infection risk. Multiple factors, including age, induce vaginal microbial alterations, characterized by high microbial diversity that generate high concentrations of short-chain fatty acids (SCFAs), known to modulate neutrophil function. However, how SCFAs may modulate innate anti-HIV protection by neutrophils is unknown. To investigate SCFA-mediated alterations of neutrophil function, blood neutrophils from younger and older women were treated with SCFAs (acetate, butyrate and propionate) at concentrations within the range reported during bacterial vaginosis, and phenotype, migration and anti-HIV responses were evaluated. SCFA induced phenotypical changes preferentially in neutrophils from older women. Butyrate decreased CD66b and increased CD16 and CD62L expression, indicating low activation and prolonged survival, while propionate increased CD54 and CXCR4 expression, indicating a mature aged phenotype. Furthermore, acetate and butyrate significantly inhibited neutrophil migration in vitro and specifically reduced α-defensin release in older women, molecules with anti-HIV activity. Following HIV stimulation, SCFA treatment delayed NET release and dampened chemokine secretion compared to untreated neutrophils in younger and older women. Our results demonstrate that SCFAs can impair neutrophil-mediated anti-HIV responses.

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Section: Introductionmentioning

confidence: 99%

Short-Chain Fatty Acids Impair Neutrophil Antiviral Function in an Age-Dependent Manner

Carrillo‐Salinas

Parthasarathy

Lara

et al. 2022

Cells

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“…The immune response of cervical mucosa is affected by the menstrual cycle (62). A "window of vulnerability" to HIV-infection during the secretory phase has been proposed (63). The majority of tissue donors in this study were older than 45 years, i.e., premenopausal or menopausal.…”

Section: Discussionmentioning

confidence: 96%

Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study

et al. 2021

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Genital mucosal transmission is the most common route of HIV spread. The initial responses triggered at the site of viral entry are reportedly affected by host factors, especially complement components present at the site, and this will have profound consequences on the outcome and pathogenesis of HIV infection. We studied the initial events associated with host-pathogen interactions by exposing cervical biopsies to free or complement-opsonized HIV. Opsonization resulted in higher rates of HIV acquisition/infection in mucosal tissues and emigrating dendritic cells. Transcriptomic and proteomic data showed a significantly more pathways and higher expression of genes and proteins associated with viral replication and pathways involved in different aspects of viral infection including interferon signaling, cytokine profile and dendritic cell maturation for the opsonized HIV. Moreover, the proteomics data indicate a general suppression by the HIV exposure. This clearly suggests that HIV opsonization alters the initial signaling pathways in the cervical mucosa in a manner that promotes viral establishment and infection. Our findings provide a foundation for further studies of the role these early HIV induced events play in HIV pathogenesis.

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“…The cDCs are further divided into mainly the cDC1 and cDC2 subtypes 62 . The cDC2 subtype is the more abundant cell type of the DC subsets in the blood, tissues, and lymphoid organs 63 . The two cDC subtypes are functionally different, with cDC1 being more proficient at antigen cross-presentation and, therefore, more effective at activating both CD4+ and CD8+ T cells.…”

Section: Dendritic Cell Subtypesmentioning

confidence: 99%

“…In addition to the enrichment of cells that maintain tolerance in the intestinal tissue, it is also enriched for Th17 cells, which depending on environmental conditions can be involved in maintaining epithelial integrity or inflammation 77,78 . The DCs in the intestine are divided into subtypes that differ with respect to the expression of CX3CR1, the integrin CD103, and SIRPα 63,76,79 . The most abundant DC in the colon is the CD103+ SIRPα+ subtype; the high-level expression of CCR7 on this subset suggests that they are migratory.…”

Section: Gastrointestinal Immunitymentioning

confidence: 99%

HIV-1 Exploitation of Dendritic Cell Functionality and Initial Responses in Mucosal Tissues : Elucidation of Influence of HIV-1 Complement Opsonization, and HIV-1-HSV-2 Co-infection

Svanberg

2023

Linköping University Medical Dissertations

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Human immunodeficiency virus (HIV)-1 is transmitted between individuals via sexual intercourse or via blood products. To date there are 38 million people living with chronic HIV infection and around 1.5 million yearly acquire a new infection. HIV is known to have detrimental effects on the immune system and its cell function and leads to the development of acquired immune deficiency syndrome (AIDS). AIDS is characterized by opportunistic infections often fatal to the individual. Mucosal tissues, which are the main site of HIV-1 infection, consist of a complex network of different cell types building up a barrier against the outside world. In the mucosa there are multiple immune cells and one of them is the dendritic cells (DCs), a professional antigen presenting cell needed for priming of adaptive T cell responses. DCs are rarely productively infected with HIV-1 but the virus can modulate the DC phenotype and function by mere exposure to the virus. There are many factors that influence viral transmission including prevalent inflammatory conditions or infections in the genital tract. For instance, a newly acquired herpes simplex virus-2 (HSV-2) infection increases the risk of transmission at HIV-1 exposure by four times. A vital part of the innate immune defense is the complement system, which consists of proteins found in all body fluids. Normally during complement activation, it leads to lysis of pathogens, but HIV-1 can evade this process. This is achieved by the incorporated complement regulatory proteins in the viral plasma membrane leading to accumulation of opsonizing complement fragments on the HIV-1 particles. Our aim with these studies was to deepen the understanding of the HIV-1 exploitation of DC function and elucidate the initial effects exposure and establishment of HIV-1 infection has on the mucosal tissues and immune cells. In addition, we aimed to elucidate the effects HSV-2 exerts on the HIV-1-infection of DCs and how viral complement opsonization affects the viral infection and activation of immune responses. In Paper I we found that coinfection of monocyte derived DCs (MDDCs) with HIV-1 and HSV-2 decreases the amount of the HIV-1 restriction factors SAMHD1 and TREX1 in MDDCs, leading to increased productive HIV-1 infection. In Paper II and III we found that HIV-1 utilizes the complement system to induce higher productive infection of the colorectal and cervical mucosal DCs. The different forms of HIV, free or complement opsonized, had distinct effects on the immune responses and T cell phenotypes in the tissues, all in favor of HIV-1 establishment and productive infection. In Paper IV, HIV-1 exposed DCs triggered after crosstalk with suppressive T cells a prolonged type I interferon response and an upregulation of coinhibitory molecules on the DCs. The findings in this thesis add to the knowledge of HIV-1 early transmission events, how co-infection modulates DC function, and how the presence of HIV-1 affects the priming of adaptive immune responses.

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HIV Pathogenesis in the Human Female Reproductive Tract

Cited by 15 publications

References 239 publications

Short-Chain Fatty Acids Impair Neutrophil Antiviral Function in an Age-Dependent Manner

Short-Chain Fatty Acids Impair Neutrophil Antiviral Function in an Age-Dependent Manner

Complement-Opsonized HIV Modulates Pathways Involved in Infection of Cervical Mucosal Tissues: A Transcriptomic and Proteomic Study

HIV-1 Exploitation of Dendritic Cell Functionality and Initial Responses in Mucosal Tissues : Elucidation of Influence of HIV-1 Complement Opsonization, and HIV-1-HSV-2 Co-infection

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