CD4+ T lymphocytes are a specialized subpopulation of T cells that recognize antigenic peptides in the context of MHC class II molecules. Historically, CD4+ T cells have been regarded as 'helper' T (Th) cells, since CD4+ T-cell help is required for both the induction of neutralizing antibodies by mature B cells and for the maintenance of effective cytotoxic T cell (CTL) responses. In the mid-1980s functional attributes were discovered that allowed CD4+ T cells to be subdivided into dichotomous subpopulations of Th1 and Th2 cells .
Th1 cells are defined by their property to produce IFNγ, TNFα and IL-2 cytokines, and play critical roles in anti-tumor immunity  and immune responses to many virus infections including lymphocytic choriomeningitis virus (LCMV) , influenza virus , vesicular stomatitis virus (VSV) , polio virus , and murine γ herpes virus . Besides helper functions, Th1 cells also have important effector functions. For example, in addition to their immunoregulatory activities, both IFNγ and TNFα cytokines mediate direct anti-viral activities as observed in murine infections of LCMV , herpes simplex virus (HSV) , vaccinia virus , measles virus (MV)  and Friend virus (FV) . Th1 cells may also have cytotoxic potential as observed in a number of viral infections, including dengue virus , HSV , hepatitis B virus (HBV) , MV , human herpesvirus 6 , HIV  and Epstein-Barr virus (EBV) .
By contrast, Th2 cells secrete IL-4, IL-5, IL-9, IL-13 and IL-25 when activated in response to bacterial, helminth or parasitic pathogens such as Clostridium tetani, Staphylococcus aureus, Streptococcus pneumonia, Pneumocystis carinii, Schistosoma mansoni, and Trichinella spiralis . Th2 cells provide help for B cells to produce IgM, IgA, IgE, and IgG isotype antibodies, which form the effector molecules of the humoral immune response .
The Th1/Th2 paradigm introduced by Mossman and Coffman has been expanded by identification of other CD4+ T cell sub-populations. IL-17 secreting cells designated as Th17 cells [22, 23] are important for resistance to extracellular bacteria and fungi, but may also contribute to allergic responses  and autoimmune pathogenesis in diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis and inflammatory bowel disease . Yet another sub-population of CD4+ T cells is the follicular helper T (Tfh) cell. Upon antigenic stimulation, Tfh produce IL-21 and home to B cell follicles where they are essential for the differentiation of B cells into germinal center B cells and antibody secreting plasma cells [26, 27].
Finally, there is a unique subset of CD4+ T cells called regulatory T cell (Tregs) subset that negatively regulates the immune system and serves to prevent autoimmunity and immunopathology . During many different types of infection natural and/or induced Tregs expand to control the pathogen-specific effector T cell response. Evidence indicates that this negative control mechanism is important in limiting T-cell-mediated collateral damage that may occur during immune responses against microbial pathogens. Along these lines, Tregs inhibit the development of immunopathogenesis in Hepatitis C virus (HCV) infections , HSV infections [30, 31], and FV infections . On the other hand, Treg-mediated suppression of immune responses may delay pathogen clearance as observed in chronic HCV [33–35], HIV , EBV , HSV , and FV  infections. In the same context, Tregs also inhibit anti-tumor immune responses and restoration of anti-tumor immunity requires attenuation of Treg functions .
The general importance of CD4+ T cells in human health and immunity was dramatically displayed early in the AIDS epidemic as patients presenting with reduced CD4+ T cell counts developed opportunistic infections. CD4+ T cells, the main targets for HIV infection, are rapidly depleted during HIV infection [41, 42], eventually leading to the acquired immunodeficiency syndrome known as AIDS. Loss of antiviral IFNγ production by CD4+ T cells, as well as loss of direct cytotoxic activity against infected cells [43–45], contribute to immunodeficiency, but more important may be the loss of CD4+ T cell helper activity. CD4+ T cell help is necessary for long-term CD8+ T cell memory and the development of high-avidity antibody responses, both of which are deficient in HIV infections [46–48]. Another major factor contributing to HIV-induced immunodeficiency is immune system hyperactivation, which appears to be the result of HIV-induced pathology in the gut-associated lymphoid tissue [49, 50]. Damage to the gastrointestinal tract early in HIV infection allows immunostimulatory microbial products such as lipopolysaccharide to translocate into the bloodstream . The resulting non-specific activation of immune cells can cause activation-induced cell death and contribute to HIV-associated CD4+ T cell depletion. This dysregulation of the immune response not only reduces the ability to mount pathogen-specific responses, but can cause immunopathogenic effects. Dysregulation is further exacerbated by the loss of CD4+ Tregs, which would normally dampen immunopathogenic responses [52, 53].
The reported loss of CD4+ Tregs from the peripheral blood in HIV patients , is associated with an accumulation of these same cells in infected lymphatic tissues, suggesting that Tregs either redistribute to infected tissues, proliferate there, or both [36, 55]. Tregs at the sites of infection are associated with dysfunctional CD8+ T cells and can inhibit both HIV-specific CD4+ and CD8+ T cell responses in vitro [36, 54, 56]. Interestingly, HIV-infected patients who exert control over virus loads have lower Treg responses , suggesting that Tregs indeed contribute to effector T cell dysfunction and inability to clear the infection.
Acute HIV-1 infection is usually characterized by mild flu-like symptoms and hence, only few patients are diagnosed with acute HIV infection. Thus, there is limited opportunity to study the early immunological responses to HIV infection. Another limitation in HIV research is the lack of a tractable small animal model susceptible to HIV infection. The most widely used model is the infection of macaques with simian immunodeficiency virus (SIV), which is closely related to HIV, and an enormous amount of knowledge has been gained from studies in this model. However, there are limitations in the studies that can be done in non-human primates as compared to a mouse model. For example, there are no colonies of congenic, transgenic, or targeted gene knockout macaques available for study. Since there is no perfect solution for scientists to study HIV infections, the approach has been to gain information from studies in humans, non-human primates, and also mouse models, which are useful for elucidating fundamental concepts in retroviral immunology that may have relevance to HIV infections in humans.
A mouse virus that has been particularly informative is the Friend retrovirus, which has provided information regarding basic mechanisms of immunological control and escape in both acute and persistent retroviral infections. Studies of mice infected with FV have revealed a complex balance of immune responses induced by at least two subsets of CD4+ T cells with opposing effects. On one hand, CD4+ Tfh and Th1 cells coordinate B cell and CD8+ T cell immune responses, and additionally induce direct anti-viral effects fortifying the immunological control of FV [57–59]. On the other hand, CD4+ Tregs down-regulate the immune responses of CD4+ Th cells [32, 58] and CD8+ CTLs [39, 60–62] thus, prolonging the recovery from acute FV infection, and allowing the establishment of a chronic infection. The interplay of different subsets of CD4+ T cells in FV infection and the relevance to HIV infection in humans will be discussed in this review.