Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

HIV-Associated Bacterial Pneumonia

“…In the cell cytoplasm, viral RNA is recognized by intracellular pathogen recognition receptors known as Toll-like receptors (TLRs)-7 and -9 [20][21][22][23], and possibly by the more recently described cytoplasmic pathogen nucleic acid sensors [24]. This leads, in turn, to excessive and sustained production of: i) type I interferon (IFN); ii) the tryptophan catabolizing enzyme, indoleamine 2,3-dioxygenase; and iii) the cytokine, transforming growth factor β (TGF-β), all of which contribute to immune dysfunction [20,[25][26][27][28][29][30][31][32][33]. These immunosuppressive mechanisms are summarized in Table 1.…”

Cardiovascular Disease, Statins, and HIV

“…Finally, in some patients, deemed immune nonresponders, the CD4 + T-cell count does not rise to near-normal levels despite prolonged viral suppression [15,16]. These patients have higher levels of inflammation and immune activation markers, with presumably comparable degrees of subdetectable viral persistence, implicating a permanent residual impact of host immunity that may be due to thymic fibrosis, lymphoid organ fibrosis, irreversible loss of mucosal immunity, T-cell exhaustion, or other mechanisms [17][18][19][20][21][22][23].…”

HIV infection, lymphoid fibrosis, and disease

“…The study shows excellent response rates, deep and durable responses, continued responses during treatment, and limited severe toxicities. 1 …”

“…To determine with more precision the source of these proteins, Zeng et al used antibodies to specifically deplete CD4 ϩ or CD8 ϩ T cells, and found that the loss of the former was causally associated with reduced lymphotoxin production and the loss of the FRC network. 1 In addition, the natural hosts of SIV infection, which typically maintain normal T-cell homeostasis despite high-level viremia, have an intact FRC network. Finally, in a nice work of pure translational investigation, Zeng et al observed that treatment of cancer with chemotherapy or radiation causes CD4 ϩ T-cell depletion and damage to the FRC, an observation that can be explained by many mechanisms but which is generally consistent with the nonhuman primate data.…”

“…4,10,11 Fortunately, the model of disease pathogenesis provided by Zeng and colleagues can direct clinical investigators toward a number of potential interventions that can reverse 1 or both of the aforementioned self-perpetuating cycles. 1 These experimental interventions include drugs that remove pro-inflammatory pathogens and microbial products (eg, valganciclovir for CMV, rifaximin for gut microbes, sevelamer for lipopolysaccharide), drugs that directly prevent fibrosis (eg, angiotensin II receptor antagonists and ACE inhibitors), and drugs that have more broad effects in reducing inflammation (eg, statins, nonsteroidal antinflammatory drugs, methotrexate, and mesalamine). Because disease is often easier to prevent than treat and the untreated phase of the infection is associated with persistent, highlevel inflammation and presumably progressive lymphoid fibrosis, then a reasonable conclusion from the body of work summarized here is for patients to start antiretroviral therapy as soon as possible.…”