Lumbar punctures were done on 114 consecutive active duty patients referred for evaluation of positive tests for antibodies to the human immunodeficiency virus (HIV). Eighty-eight percent of these patients appeared to have early HIV infections, as evidenced by intact delayed hypersensitivity, T helper lymphocyte counts greater than 400/mm3, and lack of constitutional symptoms. Forty-four (38.6%) of the patients met our criteria for abnormal cerebrospinal fluid (CSF); another 13 (11.4%) had borderline elevations of nucleated cells or protein and could not be definitely classified as having normal or abnormal CSF. No significant differences existed between the patients with normal and abnormal CSF with regard to age; sex; race; serum FTA-Abs; clinical staging; absolute T helper lymphocyte counts; or cytomegalovirus, Toxoplasma, or Epstein-Barr virus serologies. Seventy-two percent of the patients with abnormal CSF had evidence of possible viral infection of the central nervous system (CNS), as evidenced by increased CSF IgG, increased IgG synthesis rates, or the presence of oligoclonal bands. We found that a significant percentage of asymptomatic patients with apparent early HIV infections have abnormal CSF that is possibly due to CNS involvement by HIV.
Tertiary lymphoid structures (TLS), also known as ectopic lymphoid structures (ELS) or tertiary lymphoid organs (TLO), represent a unique subset of lymphoid tissues noted for their architectural similarity to lymph nodes, but which conditionally form in peripheral tissues in a milieu of sustained inflammation. TLS serve as regional sites for induction and expansion of the host B and T cell repertoires via an operational paradigm involving mature dendritic cells (DC) and specialized endothelial cells (i.e. high endothelial venules; HEV) in a process directed by TLS-associated cytokines and chemokines. Recent clinical correlations have been reported for the presence of TLS within tumor biopsies with overall patient survival and responsiveness to interventional immunotherapy. Hence, therapeutic strategies to conditionally reinforce TLS formation within the tumor microenvironment (TME) via the targeting of DC, vascular endothelial cells (VEC) and local cytokine/chemokine profiles are actively being developed and tested in translational tumor models and early phase clinical trials. In this regard, a subset of agents that promote tumor vascular normalization (VN) have been observed to coordinately support the development of a pro-inflammatory TME, maturation of DC and VEC, local production of TLS-inducing cytokines and chemokines, and therapeutic TLS formation. This mini-review will focus on STING agonists, which were originally developed as anti-angiogenic agents, but which have recently been shown to be effective in promoting VN and TLS formation within the therapeutic TME. Future application of these drugs in combination immunotherapy approaches for greater therapeutic efficacy is further discussed.
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