T cells establish and maintain CNS viral infection in HIV-infected humanized mice
Jenna B. Honeycutt, Baolin Liao, Christopher C. Nixon, Rachel A. Cleary, William O. Thayer, Shayla L. Birath, Michael D. Swanson, Patricia Sheridan, Oksana Zakharova, Francesca Prince, JoAnn Kuruc, Cynthia L. Gay, Chris Evans, Joseph J. Eron, Angela Wahl, J. Victor Garcia
Jenna B. Honeycutt, Baolin Liao, Christopher C. Nixon, Rachel A. Cleary, William O. Thayer, Shayla L. Birath, Michael D. Swanson, Patricia Sheridan, Oksana Zakharova, Francesca Prince, JoAnn Kuruc, Cynthia L. Gay, Chris Evans, Joseph J. Eron, Angela Wahl, J. Victor Garcia
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Research Article AIDS/HIV Infectious disease

T cells establish and maintain CNS viral infection in HIV-infected humanized mice

Abstract

The human brain is an important site of HIV replication and persistence during antiretroviral therapy (ART). Direct evaluation of HIV infection in the brains of otherwise healthy individuals is not feasible; therefore, we performed a large-scale study of bone marrow/liver/thymus (BLT) humanized mice as an in vivo model to study HIV infection in the brain. Human immune cells, including CD4+ T cells and macrophages, were present throughout the BLT mouse brain. HIV DNA, HIV RNA, and/or p24+ cells were observed in the brains of HIV-infected animals, regardless of the HIV isolate used. HIV infection resulted in decreased numbers of CD4+ T cells, increased numbers of CD8+ T cells, and a decreased CD4+/CD8+ T cell ratio in the brain. Using humanized T cell–only mice (ToM), we demonstrated that T cells establish and maintain HIV infection of the brain in the complete absence of human myeloid cells. HIV infection of ToM resulted in CD4+ T cell depletion and a reduced CD4+/CD8+ T cell ratio. ART significantly reduced HIV levels in the BLT mouse brain, and the immune cell populations present were indistinguishable from those of uninfected controls, which demonstrated the effectiveness of ART in controlling HIV replication in the CNS and returning cellular homeostasis to a pre-HIV state.

Authors

Jenna B. Honeycutt, Baolin Liao, Christopher C. Nixon, Rachel A. Cleary, William O. Thayer, Shayla L. Birath, Michael D. Swanson, Patricia Sheridan, Oksana Zakharova, Francesca Prince, JoAnn Kuruc, Cynthia L. Gay, Chris Evans, Joseph J. Eron, Angela Wahl, J. Victor Garcia

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Figure 7

ART effectively controls HIV-1 infection in the brain of BLT humanized mice.

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ART effectively controls HIV-1 infection in the brain of BLT humanized m...
(A) HIV DNA and (B) HIV RNA levels in the brains of HIV-infected/-untreated (n = 52 DNA, 82 RNA) and HIV-infected/ART-treated (n = 17 DNA and 36 RNA) BLT mice. Dashed horizontal lines represent the lower limit of detection for cell-associated DNA and RNA (~4 copies). A Mann-Whitney U test was used to compare data in A and B. (C) Scatter plot depicts the HIV RNA levels in the plasma and brains of HIV-infected/ART-treated BLT mice (n = 36). Dashed vertical line represents the lower limit of detection for the plasma VL (~688 RNA copies/ml plasma). A Spearman’s rank correlation test was used to analyze the data in C. Absolute numbers of human (D) hematopoietic cells (n = 104, 101, and 44), (E) T cells (n = 97, 101, 44), (F) CD4+ T cells (n = 97, 101, and 44), (G) CD8+ T cells (n = 97, 101, and 44), (H) the CD4+/CD8+ T cell ratio (n = 97, 101, and 44), and (I) the numbers of human myeloid cells (n = 97, 86, and 44) in the brains of uninfected (from Figure 3), HIV-infected/-untreated (from Figure 6), and HIV-infected/ART-treated mice were determined by flow cytometry. In D–I, the n values for uninfected, HIV-infected/-untreated, and HIV-infected/ART-treated groups are indicated in parentheses from left to right. The data in D–I were analyzed using a Kruskal-Wallis test, with Dunn’s post test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.