Human Immunodeficiency Virus Biology And General Medical Overview Of Seroconversion And Early Infection

Pathogenesis and Pathophysiology. HIV-1, the etiological agent of AIDS, is a non-oncovirus ribonucleic acid (RNA) retrovirus that belongs to the lentivirinae genus of the Retroviridae family. Lentiviruses are species specific, having long periods of clinical latency and mechanisms to evade immune clearance. They target specific organs and cause persistent infection and multisystem disease in their natural hosts. Lentiviruses characteristically cause neurological disease.

HIV-1, as other human retroviruses, is an enveloped virus containing RNA genomes of positive polarity. Structurally, HIV-1 is similar to other retroviruses ( .Fig, 44-1 ).

Figure 44-1 A schematic depiction of the HIV-1 virion. Virion protein components of the envelope and nucelocapsid are indici(Modified from Greene WC: The molecular biology of human immunodeficiency virus type 1 infection. N Engl J Med 1991;324:308-317.)

There are two copies of the single-stranded RNA and polymerase in the central cylindrical core, which also contains four nucleocapsid proteins, p24, p17, p9, and p7. The nucleoprotein core is surrounded by a lipid bilayer membrane. The viral genome contains three major segments coding for the structural proteins: GAG (the internal core protein), POL (the polymerase), and ENV (the envelope protein complex) ( Fig. 44-2 ). These are situated in a left-to-right 5 -to-3

order. The GAG gene encodes the internal core proteins of the virion particle. The POL gene encodes the polymerase reverse transcriptase, a ribonuclease that copies the viral rNa into DNA, a ribonuclease (RNase H) that degrades the viral RNA once an initial DNA copy has been synthesized, and an endonuclease (intergrase) that is responsible for integration of the DNA copy into the host cell chromosome. POL also encodes a protease that is required for the processing of the mature GAG and POL products from their polyprotein precursors during virion assembly. The ENV gene codes for the surface envelope glycoprotein complex, gp120/gp41, which mediates binding of the virus to the host target cell. Long terminal repeats are situated at each end of the retroviral genome and are involved in the regulation of viral expression and the initiation and termination of viral RNA transcription.

In general, retroviruses capable of replication contain only three genes ( GAG, POL, and ENV). However, the viral genome of HIV-1 is more complex and contains additional genes for regulatory proteins. TAT and REV regulate viral gene expression and are essential for virus replication. TAT, a transcriptional activator, stimulates the synthesis of HIV messenger RNAs early in the viral life cycle. REV modulates the pattern of viral RNAs expressed in infected cells and allows ordered production of viral proteins during the virus life cycle. The genes termed VIF, VPR, VPR, and NEF encode products that enhance the ability of the virus to productively infect host target cells and maximize the efficiency of viral replication. It is believed that the actions of these "additional" genes contribute to HIV-1's pathogenicity.

The outer envelope of HIV-1 is derived from the host cell lipid bilayer during viral budding and in which viral

Figure 44-2 HIV-1 genomic structure. (Modified from Staprans SI, Feinberg MB: Natural history and immunopathogenesis of HIV-1 disease.ln Sande MA, Volberding PA [eds]. The Medical Management of AIDS, 5th ed. Philadelphia, W.B. Saunders, 1997, pp 29-55.)

glycoproteins (coded by the gene, ENV) are inserted. Electron microscopy has revealed that the HIV virion has an icosahedral structure containing 72 external spikes. These envelope spikes are responsible for binding to the receptor on the host cell and are important in cellular entry. They are composed of two components, gp120/gp41. Gp120, the external protein, contains the receptor-binding determinants of the virus. The transmembrane protein, gp41, serves to anchor the envelope glycoprotein complex at the surface of the viral lipid bilayer and is responsible for cell entry through fusion with the cell membrane. The HIV-1 lipid bilayer also contains host proteins including class I and class II histocompatibility antigens acquired during viral budding. Once within the cytoplasm of the host cell,

Figure 44-3 (Figure Not Available) The human immunodeficiency virus life cycle (RNA-binding proteins: Tat, Rev; Retroviral genes: env, nef, gag, pol; RT, reverse transcrip(Reproduced with permission from Folks TM, Hart CE: The life cycle of human immunodeficiency virus type I. In DeVita VT, Hellman S, Rosenberg SA [eds]. AIDS: Biology, Diagnosis, Treatment and Prevention, 4th ed. Philadelphia, Lippincott-Raven, 1997, p 31.)

the envelope of the virus is shed, its contents are released, and reverse transcription occurs. Reverse transcriptase enables the transcription of DNA from genomic RNA (contrary to the conventional informational flow from DNA to RNA to protein). The provirus DNA is then integrated into the host cell's DNA, where it may replicate, remain latent, or replicate at a restricted rate. When activated, the proviral DNA transcribes genomic and messenger RNA (Fig. 44-3 (Figure Not Available) ). After the viral proteins are synthesized, new virions are assembled. The virus matures by budding from the surface of cells or into vacuoles within the cells.

HIV-1 targets, infects, and damages cells that have critically important functions in the host immune response. Cell types susceptible to HIV-1 infection, in vitro and in

Figure 44-4 HIV-1 natural history. (Modified from Staprans SI, Feinberg MB: Natural history and immunopathogenesis of HIV-1 disease.In Sande MA, Volberding PA [eds]. The Medical Management of AIDS, 5th ed. Philadelphia, W.B. Saunders, 1997, pp 29-55.)

vivo, are those that express the CD4+ surface receptor. This target cell preference results from the identity (high affinity binding) of HIV-1 gp120 to the receptor molecule, CD4+, that is used by HIV-1 during the initial stages of virus infection of host cells. Human CD4+ T-lymphocytes, monocytes/macrophages, and dendritic cells are the major cellular targets of HIV-1 infection in vivo. y The CD4+ T- cell molecule is essential in interactions between helper- inducer T lymphocytes and antigen-presenting cells. It facilitates efficient recognition of antigens by CD4+ T cells, an obligate step in the generation of host immune responses. CD4+ lymphocytes serve as both essential regulators and effectors of the normal immune response. For example, they are involved in activation of macrophages, induction of cytotoxic T-lymphocyte function, natural killer and suppressor cell function, induction of B cells (dysfunction of which leads to impairment of the humoral arm of the immune system), growth and differentiation of lymphoid cells, regulation of hematopoietic colony stimulation factors, and other factors inducing nonlymphoid cell function. It is noteworthy that the CD4+ molecule is expressed at a very early stage of T cell development, even on immature thymic T cells. Therefore CD4+ T-cells appear to be susceptible to HIV-1 infection and consequent destruction at essentially all stages of differentiation. The progressive loss of these critically important cells and basic components of the immune system ultimately leads to development of profound immunodeficiency, characteristic of advanced HIV-1 infection and eventually in AIDS.

Despite the enormous wealth of information accrued during the past decade concerning molecular properties and actions of the retrovirus, many fundamental questions remain concerning immunopathogenetic events. The following overview traces some of the major events once HIV- 1 is transmitted to the host (..Fig, 44-4 ). In-depth reviews that discuss postulated HIV's virological and immunological mechanisms have been published. y The virus, free or within cells, enters the blood or lymphatic vessels and is delivered to lymphoid tissue. It is suggested that macrophages may be the first target cell of HIV-1 early after invasion. Macrophages deliver HIV-1 to lymph nodes and other lymphoid tissue and may serve as a reservoir for HIV-1. A selection of HIV-1 strains may occur during this acute infection stage. Studies of HIV-1 isolates from donor- recipient transmission pairs show that donors have heterogeneous viral populations. In contrast, viral isolates from the newly infected person are predominantly homogeneous in their envelope sequences and these viruses are mainly macrophage-tropic. y

HIV-1 then enters the lymphoid tissue and an active immune response is mounted. A preferential infection of cells that are responding to or are proliferating in response to antigenic stimulation occurs. This leads to new cycles of HIV-1 replication and target cell infection. y Viral spread occurs to T cells and macrophages, and during the weeks after the initial infection, more cells are infected and more are lost. There is an increase in viral burden and an associated decline in the CD4+ lymphocyte counts. At this point, some individuals may develop symptomatic acute primary infection with both systemic and neurological signs (see later discussion). It is believed that a host immune response, cell-mediated and humoral, is mounted and controls the infection to some degree. Clinical symptoms of the acute illness resolve, and the amount of virus in peripheral blood falls. Monocytes, macrophages, and follicular dendritic cells are able though to foster viral replication

without cell death. These cells may serve as a reservoir for the retrovirus, allowing transport and dissemination (and possibly persistent infection) of the virus to nonlymphoid tissues such as the brain and other organ systems with subsequent development of organ-specific HIV-1-related disorders. For example, HIV-1 infection of gut epithelium may contribute to the diarrhea-wasting syndrome seen commonly in patients with more advanced HIV-1 infection, whereas infection of bone marrow progenitor cells may contribute to hematological abnormalities observed clinically in symptomatic HIV-1-infected patients. HIV-1 infection of these diverse organ cells may not be mediated by the CD4+ receptor but by others such as the glycolipid galactosylceramide.

After the acute symptomatic or asymptomatic primary infection, there is a period of clinical latency. Patients enter a chronic clinically asymptomatic or minimally symptomatic period. Recent studies show that even during the clinically "latent" period of disease there is a high rate of viral expression and replication in lymphoid tissue.^ In the stage of early and intermediate HIV-1 disease (.Ta.b.!e.,.44:.2. ), the greatest concentration of HIV-1-infected cells is still found in the lymphoid organs (lymph nodes, adenoids, tonsils, spleen). There is, however, involvement of nonlymphoid tissues as well. y A very dynamic pattern of HIV-1 replication and turnover may occur. Ho et al. estimated that approximately 1 billion new virions are produced daily with replication occurring in lymph tissue. y At the same time, about 1 to 2 billion new CD4+ cells are produced. Persistence of virus in lymphoid tissue can cause chronic stimulation of the immune system. y This may lead to dysfunction and destruction of the responding T cells. Even before the occurrence of a very marked decline in CD4+ cell numbers, specific defects in T-cell function can be noted. The effect on the immune system is widespread, affecting multiple aspects of lymphocytic function, the interaction of T cell with antigen presenting cells, and disruption of lymphoid tissue architecture.

As CD4+ lymphocytes are lost as a result of virus- induced damage, the host's immune system attempts to compensate for depleted T cells by producing more cells, which become infected. It is hypothesized that homeostatic mechanisms exist to maintain a "normal" T-cell count. This hypothesis implies that the selective loss of CD4+ cells will induce production of both CD4+ and CD8+ cells in order to maintain homeostasis of T-cell number (referred to as "blind homeostasis"). CD4+ and CD8+ cells continue to be produced to maintain the total lymphocyte count as CD4+ cells are lost. This results in CD4+ cell lymphopenia and CD8+ lymphocytosis. y CD8+ lymphocytosis may in itself cause symptomatic complications. Approximately 18 months before the development of AIDS, this mechanism breaks down, resulting in lymphopenia. An increase in the rate of loss of CD4+ lymphocytes and

TABLE 44-2 -- STAGES OF HIV-1 DISEASE AS RELATED TO CD4+ COUNT

Early HIV-1 infection

CD4+

500 cells/mm3

Intermediate HIV-1 infection

CD4+ 200-500 cells/mm3

AIDS

CD4+

200 cells/mm2

perhaps in the appearance of more virulent viral phenotypes heralds the progression to AIDS.

The exact mechanisms by which HIV-1 infection leads to progressive loss of circulating CD4+ lymphocytes is not completely defined. Both direct and indirect mechanisms have been postulated. Several studies suggest that the pathogenicity of HIV-1 strains increases during the course of infection, as evidenced by the formation of a syncytial cell in vitro. y Formation of syncytia makes the cells ineffective, and there may be downregulation of CD4+ receptors. Replication of the virus depends on reverse transcriptase, and copies of the viral genome by this process are imprecise resulting in production of variant viruses during replication. This mechanism could explain the altered pathogenicity and result in the formation of syncytial cell in vitro. This process could also lead to resistance or altered sensitivity to antiviral agents. Even without the formation of syncytia, high rates of viral replication can lead to cell dysfunction and death. y Moreover, gp120 may itself activate cells, which in turn leads to production of cytokines that may adversely affect the function of other cells.

Regarding the pathophysiology of HIV-1 in children, a bimodal evolution of disease progression is noted (see later discussion). Infants with rapid disease progression (the first form) have high levels of detectable virus at birth and manifest severe clinical symptoms and immunologic abnormalities within the first years of life. Some of these infants may lack anti-HIV-1 antibodies. This rapidly progressive course may reflect the effects of HIV-1 on the developing fetal thymus and immune system. In some cases, however, high levels of viral expression is found with normal CD4+ cell counts suggesting that in this subset of children early HIV-1 thymic infection may have impaired and resulted in immunological tolerance.

In children with slowly progressive disease (the second form), there is the occurrence of more frequent and severe infections with common childhood pathogens followed later by OIs. Although the principal target of HIV-1 is the human peripheral blood CD4+ T-lymphocyte, in children one of the first immunological abnormalities is impairment of B-cell function. This is manifested by polyclonal hypergammaglobulinemia, spontaneous B-cell proliferation, and increased in vitro spontaneous production of immunoglobulin (the development of polyclonal hypergammaglobulinemia may also be noted in adults). y Although the quantity of immunoglobulins is elevated, there are diminished in vivo vaccine responses to both T-cell dependent and T-cell independent antigens as well as decreased responses to B- cell mitogens.y In vitro studies demonstrate diminished lymphocyte proliferation to B-cell mitogens. The decreased antibody responses predispose these infants and children to serious bacterial infections, which at times may be overwhelming. The B-cell activation may also result in polyclonal polymorphic B-cell lymphoproliferative disorders, such as lymphoid interstitial pneumonitis, parotitis, and unusual B-cell related complications such as B-cell lymphomas. Increased production of autoantibodies may also result from B-cell dysfunction. Circulating immune complexes, antinuclear antibodies, antibody to double-stranded DNA, red cell antibodies, and antiplatelet antibodies have been reported.

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