Publicação
In vitro infection of lymphoid tissues by HIV-2
| Resumo: | Lymphoid organs constitute an optimal environment for the defense against the invasion of pathogens by promoting immune responses. They are the major reservoirs of human immunodeficiency virus (HIV) infection, however their infection has only been focused in the context of HIV-1. HIV-2 represents a more attenuated form of HIV disease, characterized by slower CD4+ T cell decline and progression to AIDS, that doesn’t have the same impact worldwide as HIV-1. Nevertheless, HIV-2 constitutes a unique naturally occurring model of attenuated HIV disease valuable for the study of HIV pathogenesis. Understanding the impact of HIV-2 infection on lymphoid organs will provide new insights regarding the ability of the tissue to promote immune responses. Here we investigated the impact of HIV-2 in human tonsillar tissue, a secondary lymphoid organ (SLO). Tonsil organ cultures (TOCs) were infected with HIV-2 or HIV-1 primary isolates using either CCR5 (R5) or CXCR4 (X4) coreceptors. All viruses were able to replicate in the tissue, as revealed by immunohistochemistry. In addition, we found that HIV-2-infected lymphocytes from TOCs presented similar levels of total HIV DNA as HIV-1. Surprisingly, Gag mRNA and protein levels were significantly higher in tissue infection by HIV-1 X4 as compared to R5-tropic HIV-1 or HIV-2, suggesting that the viral production observed in TOCs may be due to the infection of other cells in the tissue, and that viral transcriptional regulation may be altered in X4-tropic HIV-2. Interestingly, despite the lower lymphocyte-associated viral replication observed with X4-tropic HIV-2, the impact on the viability of CD4+ T cells and on the memory CD4+ T cell compartment was similar to that observed with HIV-1 X4. Moreover, we found that infection of TOCs with X4-tropic viruses resulted in a higher frequency of cells expressing Foxp3, a molecule related with the regulatory phenotype. This was particularly observed for X4-tropic HIV-2 infection and was not related with cell proliferation. In addition, we observed a significantly higher depletion of follicular cells within Foxp3+ cells in TOCs infected with X4-tropic HIV-2, indicating higher persistence of Foxp3+ Tregs. Finally, we observed that all viruses were able to deplete the T follicular helper (TFH) subset, a subset that is essential for B cell differentiation. In conclusion, our data showed that HIV-2 is able to infect lymphoid tissue in a coreceptor-dependent manner, but that the replication cycle was impaired in lymphocytes at the transcriptional level. These findings on in vitro infection of lymphoid tissues by HIV-2 will provide new insights regarding HIV immunopathogenesis. |
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| Autores principais: | Antão, Ana Isabel Vieira |
| Assunto: | Lymphoid organs human tonsillar tissue in vitro organ cultures HIV-1 and HIV-2 infection Teses de mestrado - 2016 |
| Ano: | 2016 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Lymphoid organs constitute an optimal environment for the defense against the invasion of pathogens by promoting immune responses. They are the major reservoirs of human immunodeficiency virus (HIV) infection, however their infection has only been focused in the context of HIV-1. HIV-2 represents a more attenuated form of HIV disease, characterized by slower CD4+ T cell decline and progression to AIDS, that doesn’t have the same impact worldwide as HIV-1. Nevertheless, HIV-2 constitutes a unique naturally occurring model of attenuated HIV disease valuable for the study of HIV pathogenesis. Understanding the impact of HIV-2 infection on lymphoid organs will provide new insights regarding the ability of the tissue to promote immune responses. Here we investigated the impact of HIV-2 in human tonsillar tissue, a secondary lymphoid organ (SLO). Tonsil organ cultures (TOCs) were infected with HIV-2 or HIV-1 primary isolates using either CCR5 (R5) or CXCR4 (X4) coreceptors. All viruses were able to replicate in the tissue, as revealed by immunohistochemistry. In addition, we found that HIV-2-infected lymphocytes from TOCs presented similar levels of total HIV DNA as HIV-1. Surprisingly, Gag mRNA and protein levels were significantly higher in tissue infection by HIV-1 X4 as compared to R5-tropic HIV-1 or HIV-2, suggesting that the viral production observed in TOCs may be due to the infection of other cells in the tissue, and that viral transcriptional regulation may be altered in X4-tropic HIV-2. Interestingly, despite the lower lymphocyte-associated viral replication observed with X4-tropic HIV-2, the impact on the viability of CD4+ T cells and on the memory CD4+ T cell compartment was similar to that observed with HIV-1 X4. Moreover, we found that infection of TOCs with X4-tropic viruses resulted in a higher frequency of cells expressing Foxp3, a molecule related with the regulatory phenotype. This was particularly observed for X4-tropic HIV-2 infection and was not related with cell proliferation. In addition, we observed a significantly higher depletion of follicular cells within Foxp3+ cells in TOCs infected with X4-tropic HIV-2, indicating higher persistence of Foxp3+ Tregs. Finally, we observed that all viruses were able to deplete the T follicular helper (TFH) subset, a subset that is essential for B cell differentiation. In conclusion, our data showed that HIV-2 is able to infect lymphoid tissue in a coreceptor-dependent manner, but that the replication cycle was impaired in lymphocytes at the transcriptional level. These findings on in vitro infection of lymphoid tissues by HIV-2 will provide new insights regarding HIV immunopathogenesis. |
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