Immune dysregulation in HIV-1 infected lymphoid tissue

Lymphoid compartments are major sites for HIV-1 replication. We evaluated cytokines, chemokines and immunological effector function at the single cell level in lymphoid tissues in chronically HIV-1 infected patients. HIV-1 infected lymphoid tissue was characterized by an extensive proinflammatory activation (IL-1alpha, IL-1beta and IL-12) and vigorous Th 1 type cytokine expression (IL-2 and IFN-gamma) while Th2 cytokines remained low (IL-4 and IL-10). Treatment with highly active anti-retroviral therapy (HAART) resulted in a significant reduction of proinflammatory as well as of Th 1 type of cytokine expression in lymphoid tissue. However, the pool of HIV-1 DNA containing cells (1 5%) remained virtually unchanged even after more than one year of HAART while the initial 3-8-fold increase of CD8+ T cells was normalized.

We hypothesized that lack of elimination of HIV-1 infected cells was due to impaired cytolytic effector function in activated CD8+ T cells that normally are mediated by either Fas-L/Fas interaction or perforin/granzyme A (grA). CD8+ T cells in HIV-1 infected lymphoid tissue were found to have upregulated Fas-L and grA expression while perforin expression was not concomitantly induced. This was however not true for CD8+ T cells obtained from acutely EBV infected patients, which instead showed upregulation of both perforin and grA expression.

Our data indicated a defective cytolytic activity in CD8+ T cells at local sites of HIV-1 replication within lymphoid tissue. To elucidate the molecular mechanism involved in inhibition of perforin expression in HIV- 1 infection, we initiated short term in vitro cultures using freshly isolated peripheral blood cells from HIV-1 seronegative donors. Exogenous addition of Nef protein was found to mediate downregulation of perforin in CD8+ T cells. Sequence alignments and molecular modeling of different Nef proteins suggested that the so-called disordered loop corresponding to residues 148-178 was a likely contributor to the observed Nef-mediated downregulation of perforin expression. Macaques infected with a nef-deleted virus displayed high perforin expression within lymphoid tissues in contrast to macaques infected with the wild-type virus, which suggested a role for Nef as perforin modulator in vivo.

Furthermore, cytokine mediated regulation of chemokine receptor expression (CCR5CXCR4) was studied in placenta tissue from transmitting (TT) and non-transmitting (TNT) HIV- 1 infected women. We found upregulation of CCR5 combined with IL-2 expression both at the protein and mRNA level in placenta from TT women. This was associated with an increase in the number of gag-pol mRNA expressing cells. In contrast, the placenta from TNT women was characterised by upregulation of Th2 type (IL-4, IL- 10) cytokine expression. We found an association between Th2 type of cytokine (IL-4) expression and Leukemia Inhibitor Factor (LIF) production in placenta from TNT tissue while LIF expression was low in placenta from TT women. Therefore, we investigated whether LIF secretion may play a role in HIV-1 inhibition. LIF inhibited HIV-1 replication in a co-receptor independent manner. This inhibition was dependent upon the expression of LIF-R beta (gp 13 0) on the surface of HIV-1 susceptible cells. The identification of LIF as an inhibitor of HIV-1 replication may lead to the development of a novel anti-retroviral treatment.

List of scientific papers

I. Andersson J, Fehniger TE, Patterson BK, Pottage J, Agnoli M, Jones P, Behbahani H, Landay A (1998). Early reduction of immune activation in lymphoid tissue following highly active HIV therapy. AIDS. 12(11): F123-9.
https://pubmed.ncbi.nlm.nih.gov/9708402

II. Behbahani H, Landay A, Patterson BK, Jones P, Pottage J, Agnoli M, Andersson J, Spetz AL (2000). Normalization of immune activation in lymphoid tissue following highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 25(2): 150-6.
https://pubmed.ncbi.nlm.nih.gov/11103045

III. Andersson J, Behbahani H, Lieberman J, Connick E, Landay A, Patterson B, Sonnerborg A, Lore K, Uccini S, Fehniger TE (1999). Perforin is not co-expressed with granzyme A within cytotoxic granules in CD8 T lymphocytes present in lymphoid tissue during chronic HIV infection. AIDS. 13(11): 1295-303.
https://pubmed.ncbi.nlm.nih.gov/10449281

IV. Behbahani H, Achour A, Tjernlund A, Leitner L, Sodora DL, Nilsson J, Zhang D, Pattersson BK, Lieberman J, Andersson J, Spetz A-L (2002). HIV-1 Nef downregulates perforin expression in CD8+ T cells providing a potential mechanism for impaired cytolytic function. [Submitted]

V. Behbahani H, Popek E, Garcia P, Andersson J, Spetz AL, Landay A, Flener Z, Patterson BK (2000). Up-regulation of CCR5 expression in the placenta is associated with human immunodeficiency virus-1 vertical transmission. Am J Pathol. 157(6): 1811-8.
https://pubmed.ncbi.nlm.nih.gov/11106553

VI. Patterson BK, Behbahani H, Kabat WJ, Sullivan Y, OGorman MR, Landay A, Flener Z, Khan N, Yogev R, Andersson J (2001). Leukemia inhibitory factor inhibits HIV-1 replication and is upregulated in placentae from nontransmitting women. J Clin Invest. 107(3): 287-94.
https://pubmed.ncbi.nlm.nih.gov/11160152