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True long-term nonprogressors (LTNPs)/elite controllers (ECs) maintain durable control over HIV replication without antiretroviral therapy. Herein we describe 4 unique persons who were distinct from conventional LTNPs/ECs in that they had extraordinarily low HIV burdens and comparatively weak immune responses. As a group, typical LTNPs/ECs have unequivocally reactive HIV-1 Western blots, viral loads below the lower threshold of clinical assays, low levels of persistent viral reservoirs, an over-representation of protective HLA alleles, and robust HIV-specific CD8(+) T-cell responses. The 4 unique cases were distinguished from typical LTNPs/ECs based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels, and difficult to isolate replication-competent virus. All 4 had at least one protective HLA allele and CD8(+) T-cell responses that were disproportionately high for the low antigen levels but comparatively lower than those of typical LTNPs/ECs. These unique persons exhibit extraordinary suppression over HIV replication, therefore, higher-level control than has been demonstrated in previous studies of LTNPs/ECs. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies.

Idiopathic CD4+ T lymphocytopenia (ICL) is a rare heterogeneous disorder defined by CD4+ T-cell counts below 300 cells/muL in the absence of human immunodeficiency virus (HIV) infection or other known immune deficiency disorders. Here, we report the expansion of immature/transitional B cells in patients with ICL, which is associated with elevated serum levels of IL-7. Both the percentage of immature/transitional B cells and levels of IL-7 were inversely correlated with levels of CD4+ T-cell counts and directly correlated to each other. Further analyses of B cells indicated that, in contrast to the activating effects of HIV disease on mature B cells, the expansion of immature/transitional B cells in patients with ICL occurred at the expense of memory B cells. These findings extend previous reports on primary immunodeficiencies as well as HIV disease by suggesting that CD4+ T-cell lymphopenia has an impact on human B-cell development either directly or indirectly via the associated elevation of IL-7 levels.