cells. cd4+ t cells can also stimulate cells such as natural killer cells and macrophages via cytokines such as interferon-gamma, encouraging these cytotoxic cells to kill host cells in certain circumstances. the mechanism that killer t cells use during auto-immunity is almost identical to their response against viruses, and some viruses have been accused of causing auto-immune diseases such as type 1 diabetes mellitus. cellular auto-immune disease occurs because the host antigen recognition systems fail, and the immune system believes, by mistake, that a host antigen is foreign. as a result, the cd8+ t cells treat the host cell presenting that antigen as infected, and go on to destroy all host cells (or in the case of transplant rejection, transplant organ) that express that antigen. some of this section is a simplification. many auto-immune diseases are more complex. a well-known example is rheumatoid arthritis, where both antibodies and immune cells are known to play a role in the pathology. generally the immunology of most auto-immune diseases is not well understood. hiv infection perhaps the best example of the importance of cd4+ t cells is demonstrated with human immunodeficiency virus (hiv) infection. hiv mainly targets lymphoid cd4+ t cells, but can infect other cells that express cd4 such as macrophages and dendritic cells (both groups express cd4 at low levels). it has been proposed that during the non-symptomatic phase of hiv infection, the virus has a relatively low affinity towards t cells (and has a higher affinity for macrophages), resulting in a slow kill rate of cd4+ t cells by the immune system. this is initially compensated for via the production of new helper t cells from the thymus (originally from the bone marrow). once the virus becomes lymphotropic (or t-tropic) however, it begins to infect cd4+ t cells far more efficiently (likely due to a change in the co-receptors it binds to during infection), and the immune system is overwhelmed. studies suggest that only ~5% of the lymphoid-derived cd4 t cells targeted by hiv are permissive and become productively infected with the virus. more than 95% of the cd4 t cells that die are resting and are unable to support productive infection. these cells undergo abortive infection with hiv. cell death is triggered when the host cell detects hiv foreign dna intermediates and initiates a suicidal death pathway in an attempt to protect the host, leading to caspase-1 activation in inflammasomes, thus causing pyroptosis (a highly inflammatory form of programmed cell death). at this point chronic inflammation ensues, and functional cd4+ t cell levels begin to decrease, eventually to a point where the cd4+ t cell population is too small to recognize the full range of antigens that could potentially be detected. the depletion of cd4 t cells and the development of chronic inflammation are signature processes in hiv pathogenesis that propel progression to acquired immune deficiency syndrome (aids). cd4 t cell depleted to the cell count of less than 200cell/μl in blood during aids allows various pathogens to escape t cell recognition, thus allowing opportunistic infections that would normally elicit a helper t cell response to bypass the immune system. while these complete bypass situations only occur when the helper t cell response is absolutely necessary for infection clearance, most infections increase in severity and/or duration because the immune system's helper t cells provide less efficient immune response. two components of the immune system are particularly affected in aids, due to its cd4+ t cell dependency: cd8+ t cells are not stimulated as effectively during the aids stage of hiv infection, making aids patients very susceptible to most viruses, including hiv itself. this decline in killing of cd4+ t cells results in the virus being produced for a longer period (the infected cd4+ t cells are not killed as quickly), increasing the proliferation of the virus, and accelerating the development of the disease. antibody class switching declines significantly once helper t cell function fails. the immune system loses its ability to improve the affinity of their antibodies, and are unable to generate b cells that can produce antibody groups such as igg and iga. these effects are primarily due to the loss of any helper t cell that can interact with the b lymphocyte correctly. another symptom of aids is the reduction in antibody levels due to a decrease in th2 cytokines (and less interactions by helper t cells). all of these complications result in an increased susceptibility to aggressive bacterial infections, especially in areas of the body not accessible by igm antibodies. if the patient does not respond to (or does not receive) hiv treatment they will succumb usually to either cancers or infections; the immune system finally reaches a point where it is no longer coordinated or stimulated enough to deal with the disease. inhibition of cd4 t-cell expansion during hiv infection may occur due to microbial translocation in an il-10-dependent way. triggering pd-1 expressed on activated monocytes by its ligand pd-l1, induces il-10 production which inhibits cd4 t-cell function. covid-19 in coronavirus disease 2019 (covid-19) b cell, natural killer cell, and total lymphocyte counts decline, but both cd4+ and cd8+ cells decline to a far greater extent. indicating that sars-cov-2 attacks the cd4+ cells during infection. low cd4+ predicted greater likelihood of intensive care unit admission, and cd4+ cell count was the only parameter that predicted length of time for viral rna clearance. despite the reduced levels of cd4+, covid-19 patients with severe disease had higher levels of th1 cd4+ cells than patients with moderate disease.