Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome

Etiology

HIV-1 and HIV-2 are members of the Retroviridae family and belong to the Lentivirus genus, which includes cytopathic viruses causing diverse diseases in several animal species. The HIV-1 genome contains two copies of single-stranded RNA that is 9.2 kb in size. At both ends of the genome there are identical regions, called long terminal repeats, which contain the regulation and expression genes of HIV. The remainder of the genome includes three major sections: the GAG region, which encodes the viral core proteins (p24 [capsid protein: CA], p17 [matrix protein: MA], p9, and p6, which are derived from the precursor p55); the POL region, which encodes the viral enzymes (i.e., reverse transcriptase [p51], protease [p10], and integrase [p32]); and the ENV region, which encodes the viral envelope proteins (gp120 and gp41, which are derived from the precursor gp160). Other regulatory proteins, such as transactivator of transcription (tat: p14), regulator of virion (rev: p19), negative regulatory factor (nef: p27), viral protein r (vpr: p15), viral infectivity factor (vif: p23), viral protein u (vpu in HIV-1: P16), and viral protein x (vpx in HIV-2: P15), are involved in transactivation, viral messenger RNA expression, viral replication, induction of cell cycle arrest, promotion of nuclear import of viral reverse transcription complexes, downregulation of the CD4 receptors and class I major histocompatibility complex, proviral DNA synthesis, and virus release and infectivity ( Fig. 302.2 ).

The HIV tropism to the target cell is determined by its envelope glycoprotein (Env). Env consists of two components, namely, the surface, heavily glycosylated subunit, gp120 protein and the associated transmembrane subunit glycoprotein gp41. Both gp120 and gp41 are produced from the precursor protein gp160. The glycoprotein gp41 is very immunogenic and is used to detect HIV-1 antibodies in diagnostic assays; gp120 is a complex molecule that includes the highly variable V3 loop. This region is immunodominant for neutralizing antibodies. The heterogeneity of gp120 presents major obstacles in establishing an effective HIV vaccine. The gp120 glycoprotein also carries the binding site for the CD4 molecule, the most common host cell surface receptor of T lymphocytes. This tropism for CD4 ⁺ T cells is beneficial to the virus because of the resulting reduction in the effectiveness of the host immune system. Other CD4-bearing cells include macrophages and microglial cells. The observations that CD4 ⁻ cells are also infected by HIV and that some CD4 ⁺ T cells are resistant to such infections suggests that other cellular attachment sites are needed for the interaction between HIV and human cells. Several chemokines serve as coreceptors for the envelope glycoproteins, permitting membrane fusion and entry into the cell. Most HIV strains have a specific tropism for one of the chemokines, including the fusion-inducing molecule CXCR-4, which acts as a coreceptor for HIV attachment to lymphocytes, and CCR-5, a β chemokine receptor that facilitates HIV entry into macrophages. Several other chemokine receptors (CCR-3) have also been shown in vitro to serve as virus coreceptors. Other mechanisms of attachment of HIV to cells use nonneutralizing antiviral antibodies and complement receptors. The Fab portion of these antibodies attaches to the virus surface, and the Fc portion binds to cells that express Fc receptors (macrophages, fibroblasts), thus facilitating virus transfer into the cell. Other cell-surface receptors, such as the mannose-binding protein on macrophages or the DC-specific, C-type lectin (DC-SIGN) on dendritic cells, also bind to the HIV-1 envelope glycoprotein and increase the efficiency of viral infectivity. Cell-to-cell transfer of HIV without formation of fully formed particles is a more rapid mechanism of spreading the infection to new cells than is direct infection by the virus.

Following viral attachment, gp120 and the CD4 molecule undergo conformational changes, and gp41 interacts with the fusion receptor on the cell surface ( Fig. 302.3 ). Viral fusion with the cell membrane allows entry of viral RNA into the cell cytoplasm. This process involves accessory viral proteins (nef, vif) and binding of cyclophilin A (a host cellular protein) to the capsid protein (p24). The p24 protein is involved in virus uncoating, recognition by restriction factors, and nuclear importation and integration of the newly created viral DNA. Viral DNA copies are then transcribed from the virion RNA through viral reverse transcriptase enzyme activity, which builds the first DNA strand from the viral RNA and then destroys the viral RNA and builds a second DNA strand to produce double-stranded circular DNA. The HIV-1 reverse transcriptase is error prone and lacks error-correcting mechanisms. Thus, many mutations arise, creating a wide genetic variation in HIV-1 isolates even within an individual patient. Many of the drugs used to fight HIV infection were designed to block the reverse transcriptase action. The circular DNA is transported into the cell nucleus, using viral accessory proteins such as vpr, where it is integrated (with the help of the virus integrase) into the host chromosomal DNA and referred to as the provirus. The provirus has the advantage of latency, because it can remain dormant for extended periods, making it extremely difficult to eradicate. The infected CD4 ⁺ T cells that survive long enough to revert to resting memory state become the HIV latent reservoir where the virus persists indefinitely even in patients who respond favorably to potent antiretroviral therapy. The molecular mechanisms of this latency are complex and involve unique biologic properties of the latent provirus (e.g., absence of tat, epigenetic changes inhibiting HIV gene expression) and the nature of the cellular host (e.g., absence of transcription factors such as nuclear factor κB). Integration usually occurs near active genes, which allow a high level of viral production in response to various external factors such as an increase in inflammatory cytokines (by infection with other pathogens) and cellular activation. Anti-HIV drugs that block the integrase enzyme activity have been developed. Depending on the relative expression of the viral regulatory genes (tat, rev, nef), the proviral DNA may encode production of the viral RNA genome, which, in turn, leads to production of viral proteins necessary for viral assembly.

HIV-1 transcription is followed by translation. A capsid polyprotein is cleaved to produce the virus-specific protease (p10), among other products. This enzyme is critical for HIV-1 assembly because it cleaves the long polyproteins into the proper functional pieces. Several HIV-1 antiprotease drugs have been developed, targeting the increased sensitivity of the viral protease, which differs from the cellular proteases. The regulatory protein vif is active in virus assembly and Gag processing. The RNA genome is then incorporated into the newly formed viral capsid that requires zinc finger domains (p7) and the matrix protein (MA: p17). The matrix protein forms a coat on the inner surface of the viral membrane, which is essential for the budding of the new virus from the host cell's surface. As new virus is formed, it buds through specialized membrane areas, known as lipid rafts, and is released. The virus release is facilitated by the viroporin vpu, which induces rapid degradation of newly synthesized CD4 molecules that impede viral budding. In addition, vpu counteracts host innate immunity (e.g., hampering natural killer T-cell activity).

Full-length sequencing of the HIV-1 genome demonstrated three different groups (M [main], O [outlier], and N [non-M, non-O]), probably occurring from multiple zoonotic infections from primates in different geographic regions. The same technique identified eight groups of HIV-2 isolates. Group M diversified to nine subtypes (or clades A to D, F to H, J, and K). In each region of the world, certain clades predominate, for example, clade A in Central Africa, clade B in the United States and South America, clade C in South Africa, clade E in Thailand, and clade F in Brazil. Although some subtypes were identified within group O, none was found in any of the HIV-2 groups. Clades are mixed in some patients as a result of HIV recombination, and some crossing between groups (i.e., M and O) has been reported.

HIV-2 has a similar life cycle to HIV-1 and is known to cause infection in several monkey species. Subtypes A and B are the major causes of infection in humans, but rarely cause infection in children. HIV-2 differs from HIV-1 in its accessory genes (e.g., it has no vpu gene but contains the vpx gene, which is not found in HIV-1). It is most prevalent in western Africa, but increasing numbers of cases are reported from Europe and southern Asia. The diagnosis of HIV-2 infection is more difficult because of major differences in the genetic sequences between HIV-1 and HIV-2. Thus, several of the standard confirmatory assays (immunoblot), which are HIV-1 specific, may give indeterminate results with HIV-2 infection. If HIV-2 infection is suspected, a combination screening test that detects antibody to HIV-1 and HIV-2 peptides should be used. In addition, the rapid HIV detection tests have been less reliable in patients suspected to be dually infected with HIV-1 and HIV-2, because of lower antibody concentrations against HIV-2. HIV-2 viral loads also have limited availability. Notably, HIV-2 infection demonstrates a longer asymptomatic stage of infection and slower declines of CD4+ T-cell counts than HIV-1, as well as is less efficiently transmitted from mother to child, likely related to lower levels of viremia with HIV-2.

Epidemiology

In 2015, the World Health Organization (WHO) estimated that 1.8 million children younger than 15 yr of age worldwide were living with HIV-1 infection; the 150,000 new infections annually in children was a 70% reduction since 2000. Approximately 80% of new infections in this age-group occur in sub-Saharan Africa. These trends reflect the slow but steady expansion of services to prevent perinatal transmission of HIV to infants. Notably, there are still 110,000 deaths worldwide of children < 15 yr of age with HIV. Unfortunately, through 2016, an estimated 16.5 million children have been orphaned by AIDS, defined as having one or both parents die from AIDS.

Globally, the vast majority of HIV infections in childhood are the result of vertical transmission from an HIV-infected mother. In the United States, approximately 11,700 children, adolescents, or young adults were reported to be living with perinatally acquired HIV infection in 2014. The number of U.S. children with AIDS diagnosed each year increased from 1984 to 1992 but then declined by more than 95% to < 100 cases annually by 2003, largely from the success of prenatal screening and perinatal antiretroviral treatment of HIV-infected mothers and infants. From 2009 to 2013, there were 497 infants born with perinatally acquired HIV in the United States and Puerto Rico. Children of racial and ethnic minority groups are disproportionately overrepresented, particularly non-Hispanic African-Americans and Hispanics. Race and ethnicity are not risk factors for HIV infection but more likely reflect other social factors that may be predictive of an increased risk for HIV infection, such as lack of educational and economic opportunities. As of 2014, New York, Florida, Texas, Georgia, Illinois, and California are the states with the highest numbers of perinatally acquired cases of HIV in the United States.

Adolescents (13-24 yr of age) constitute an important growing population of newly infected individuals; in 2015, 22% of all new HIV infections occurred in this age-group, with 81% of youth cases occurring in young males who have sex with males (MSM); 8% of cases of AIDS also occurred in this age-group. Targeted efforts have decreased new cases by 18% among youth MSM from 2008 to 2014. It is estimated than 50% of HIV-positive youth are unaware of their diagnosis, the highest of any age-group. Considering the long latency period between the time of infection and the development of clinical symptoms, reliance on AIDS case definition surveillance data significantly underrepresents the impact of the disease in adolescents. Based on a median incubation period of 8-12 yr, it is estimated that 15–20% of all AIDS cases were acquired between 13 and 19 yr of age.

Risk factors for HIV infection vary by gender in adolescents. For example, 91–93% of males between the ages of 13 and 24 yr with HIV acquire infection through sex with males. In contrast, 91–93% of adolescent females with HIV are infected through heterosexual contact. Adolescent racial and ethnic minority populations are overrepresented, especially among females.

Pathogenesis

HIV infection affects most of the immune system and disrupts its homeostasis (see Fig. 302.3 ). In most cases, the initial infection is caused by low amounts of a single virus. Therefore, disease may be prevented by prophylactic drug(s) or vaccine. When the mucosa serves as the portal of entry for HIV, the first cells to be affected are the dendritic cells. These cells collect and process antigens introduced from the periphery and transport them to the lymphoid tissue. HIV does not infect the dendritic cell but binds to its DC-SIGN surface molecule, allowing the virus to survive until it reaches the lymphatic tissue. In the lymphatic tissue (e.g., lamina propria, lymph nodes), the virus selectively binds to cells expressing CD4 molecules on their surface, primarily helper T lymphocytes (CD4 ⁺ T cells) and cells of the monocyte-macrophage lineage. Other cells bearing CD4, such as microglia, astrocytes, oligodendroglia, and placental tissue containing villous Hofbauer cells, may also be infected by HIV. Additional factors (coreceptors) are necessary for HIV fusion and entry into cells. These factors include the chemokines CXCR4 (fusion) and CCR5. Other chemokines (CCR1, CCR3) may be necessary for the fusion of certain HIV strains. Several host genetic determinants affect the susceptibility to HIV infection, the progression of disease, and the response to treatment. These genetic variants vary in different populations. A deletion in the CCR5 gene that is protective against HIV infection (CCR5Δ32) is relatively common in whites but is rare in individuals of African descent. Several other genes that regulate chemokine receptors, ligands, the histocompatibility complex, and cytokines also influence the outcome of HIV infection. Usually, CD4 ⁺ lymphocytes migrate to the lymphatic tissue in response to viral antigens and then become activated and proliferate, making them highly susceptible to HIV infection. This antigen-driven migration and accumulation of CD4 cells within the lymphoid tissue may contribute to the generalized lymphadenopathy characteristic of the acute retroviral syndrome in adults and adolescents. HIV preferentially infects the very cells that respond to it (HIV-specific memory CD4 cells), accounting for the progressive loss of these cells and the subsequent loss of control of HIV replication. The continued destruction of memory CD4 ⁺ cells in the gastrointestinal tract (in the gut-associated lymphoid tissue or GALT) leads to reduced integrity of the gastrointestinal epithelium followed by leakage of bacterial particles into the blood and increased inflammatory response, which cause further CD4 ⁺ cell loss. When HIV replication reaches a threshold (usually within 3-6 wk from the time of infection), a burst of plasma viremia occurs. This intense viremia causes acute HIV infection, formerly known as acute retroviral syndrome which can present similar to the flu or mononucleosis (fever, rash, pharyngitis, lymphadenopathy, malaise, arthralgia, fatigue, elevated liver enzymes) in 50–70% of infected adults. With establishment of a cellular and humoral immune response within 2-4 mo, the viral load in the blood declines substantially, and patients enter a phase characterized by a lack of symptoms and a return of CD4 cells to only moderately decreased levels. Typically, adult patients who are not treated eventually progress to achieve a virologic set point (steady state), usually ranging from 10,000-100,000 during this clinical latency. This is in contrast to untreated infants with vertically acquired HIV who can achieve viral loads that are much higher, resulting in faster CD4 count declines and earlier onset of significant immunodeficiency. HIV rapidly responds to the immune system pressure by developing a genetically complex population (quasispecies) that successfully evades it. In addition, inappropriate use of antiretroviral treatment increases the ability of the virus to diverge even further by selecting for mutants with fitness or resistance advantages in the presence of subtherapeutic drug levels. Early HIV-1 replication in children has no apparent clinical manifestations. Whether tested by virus isolation or by PCR for viral nucleic acid sequences, fewer than 40% of HIV-1–infected infants demonstrate evidence of the virus at birth. The viral load increases by 1-4 mo, and essentially all perinatally HIV-infected infants have detectable HIV-1 in peripheral blood by 4 mo of age, except for those who may acquire infection via ongoing breast feeding.

In adults, the long period of clinical latency (8-12 yr) is not indicative of viral latency. In fact, there is a very high turnover of virus and CD4 lymphocytes (more than a billion cells per day), gradually causing deterioration of the immune system, marked by depletion of CD4 cells. Several mechanisms for the depletion of CD4 cells in adults and children have been suggested, including HIV-mediated single cell killing, formation of multinucleated giant cells of infected and uninfected CD4 cells (syncytia formation), virus-specific immune responses (natural killer cells, antibody-dependent cellular cytotoxicity), superantigen-mediated activation of T cells (rendering them more susceptible to infection with HIV), autoimmunity, and programmed cell death (apoptosis). The viral burden is greater in the lymphoid organs than in the peripheral blood during the asymptomatic period. As HIV virions and their immune complexes migrate through the lymph nodes, they are trapped in the network of dendritic follicular cells. Because the ability of HIV to replicate in T cells depends on the state of activation of the cells, the immune activation that takes place within the microenvironment of the lymph nodes in HIV disease serves to promote infection of new CD4 cells, as well as subsequent viral replication within these cells. Monocytes and macrophages can be productively infected by HIV yet resist the cytopathic effect of the virus and, with their long lifespan, explain their role as reservoirs of HIV and as effectors of tissue damage in organs such as the brain. In addition, they reside in anatomic viral sanctuaries where current treatment agents are less effective.

The innate immune system responds almost immediately following HIV infection by recognizing the viral nucleic acids, once the virus fuses to the infected cell, by the toll-like receptor 7. This engagement leads to activation of proinflammatory cytokines and interferon (IFN-α), which blocks virus replication and spread. The virus uses its Nef protein to downregulate the expression of major histocompatibility complex (MHC) and non-MHC ligands to reduce the natural killer (NK) cell–mediated anti-HIV activity. It also modulates NK cell differentiation and maturation, dysregulates cytokine production, and increases apoptosis. Although the mechanism by which the innate system triggers the adaptive immune responses is not yet fully understood, cell-mediated and humoral responses occur early in the infection. CD8 T cells play an important role in containing the infection. These cells produce various ligands (macrophage inflammatory proteins 1α and 1β, RANTES), which suppress HIV replication by blocking the binding of the virus to the coreceptors (CCR5). HIV-specific cytotoxic T lymphocytes (CTLs) develop against both the structural (ENV, POL, GAG) and regulatory (tat) viral proteins. The CTLs appear at the end of the acute infection, as viral replication is controlled by killing HIV-infected cells before new viruses are produced and by secreting potent antiviral factors that compete with the virus for its receptors (CCR5). Neutralizing antibodies appear later in the infection and seem to help in the continued suppression of viral replication during clinical latency. There are at least two possible mechanisms that control the steady-state viral load level during the chronic clinical latency. One mechanism may be the limited availability of activated CD4 cells, which prevent a further increase in the viral load. The other mechanism is the development of an active immune response, which is influenced by the amount of viral antigen and limits viral replication at a steady state. There is no general consensus about which of these two mechanisms is more important. The CD4 cell limitation mechanism accounts for the effect of antiretroviral therapy, whereas the immune response mechanism emphasizes the importance of immune modulation treatment (cytokines, vaccines) to increase the efficiency of immune-mediated control. A group of cytokines that includes tumor necrosis factor TNF-α, TNF-β, interleukin IL-1, IL-2, IL-3, IL-6, IL-8, IL-12, IL-15, granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor plays an integral role in upregulating HIV expression from a state of quiescent infection to active viral replication. Other cytokines such as IFN-γ, IFN-β, and IL-13 exert a suppressive effect on HIV replication. Certain cytokines (IL-4, IL-10, IFN-γ, transforming growth factor-β) reduce or enhance viral replication depending on the infected cell type. The interactions among these cytokines influence the concentration of viral particles in the tissues. Plasma concentrations of cytokines need not be elevated for them to exert their effect, because they are produced and act locally in the tissues. The activation of virtually all the cellular components of the immune system (i.e., T and B cells, NK cells, and monocytes) plays a significant role in the pathologic aspects of HIV infection. Further understanding of their interactions during the infection will expand our treatment options. Commonly, HIV isolated during the clinical latency period grows slowly in culture and produces low titers of reverse transcriptase. These isolates from earlier in clinical latency use CCR5 as their coreceptor. By the late stages of clinical latency, the isolated virus is phenotypically different. It grows rapidly and to high titers in culture and uses CXCR4 as its coreceptor. The switch from CCR5 receptor to CXCR4 receptor increases the capacity of the virus to replicate, to infect a broader range of target cells (CXCR4 is more widely expressed on resting and activated immune cells), and to kill T cells more rapidly and efficiently. As a result, the clinical latency phase is over and progression toward AIDS is noted. The progression of disease is related temporally to the gradual disruption of lymph node architecture and degeneration of the follicular dendritic cell network with loss of its ability to trap HIV particles. The virus is freed to recirculate, producing high levels of viremia and an increased disappearance of CD4 T cells during the later stages of disease.

The clinical course of HIV infection shows substantial heterogeneity. This variation is determined by both viral and host factors. HIV viruses that use coreceptor CXCR4 in the course of the infection are associated with an accelerated deterioration of the immune system and more rapid progression to AIDS. In addition, several known host genetic determinants (e.g., variants in the human leukocyte antigen region, polymorphisms in the CCR5 region such as CCR5Δ32) were already identified as affecting the disease course. There are likely additional host and viral factors yet to be identified that contribute to the variable course of HIV infection in individuals, as well. Three distinct patterns of disease are described in children. Approximately 15–25% of HIV-infected newborns in developed countries present with a rapid progression course, with onset of AIDS and symptoms during the first few months of life and a median survival time of 6-9 mo if untreated. In resource-limited countries, the majority of HIV-infected newborns will have this rapidly progressing disease course. It has been suggested that if intrauterine infection coincides with the period of rapid expansion of CD4 cells in the fetus, the virus could effectively infect the majority of the body's immunocompetent cells. The normal migration of these cells to the marrow, spleen, and thymus would result in efficient systemic delivery of HIV, unchecked by the immature immune system of the fetus. Thus, infection would be established before the normal ontogenic development of the immune system, causing more-severe impairment of immunity. Most children in this group have detectable virus in the plasma (median level: 11,000 copies/mL) in the first 48 hr of life. This early evidence of viral presence suggests that the newborn was infected in utero. The viral load rapidly increases, peaking by 2-3 mo of age (median: 750,000 copies/mL) and staying high for at least the first 2 yr of life.

Sixty percent to 80% of perinatally infected newborns in high resource countries present with a much slower progression of disease, with a median survival time of 6 yr representing the second pattern of disease. Many patients in this group have a negative PCR in the first week of life and are therefore considered to be infected intrapartum. In a typical patient, the viral load rapidly increases, peaking by 2-3 mo of age (median: 100,000 copies/mL) and then slowly declines over a period of 24 mo. The slow decline in viral load is in sharp contrast to the rapid decline after primary infection seen in adults. This observation can be explained only partially by the immaturity of the immune system in newborns and infants.

The third pattern of disease occurs in < 5% of perinatally infected children, referred to as long-term survivors or long-term nonprogressors, who have minimal or no progression of disease with relatively normal CD4 counts and very low viral loads for longer than 8 yr. Mechanisms for the delay in disease progression include effective humoral immunity and/or CTL responses, host genetic factors (e.g., human leukocyte antigen profile), and infection with an attenuated (defective-gene) virus. A subgroup of the long-term survivors called elite survivors or elite suppressors has no detectable virus in the blood and may reflect different or greater mechanisms of protection from disease progression. Note that both groups warrant long-term close follow-up because later in their course they may begin to progress with their disease.

HIV-infected children have changes in the immune system that are similar to those in HIV-infected adults. Absolute CD4 cell depletion may be less dramatic because infants normally have a relative lymphocytosis. A value of 750 CD4 cells/µL in children younger than 1 yr of age is indicative of severe CD4 depletion and is comparable to < 200 CD4 cells/µL in adults. Lymphopenia is relatively rare in perinatally infected children and is usually only seen in older children or those with end-stage disease. Although cutaneous anergy is common during HIV infection, it is also frequent in healthy children younger than 1 yr of age, and thus its interpretation is difficult in infected infants. The depletion of CD4 cells also decreases the response to soluble antigens such as the in vitro mitogens phytohemagglutinin and concanavalin A.

Polyclonal activation of B cells occurs in most children early in the infection, as evidenced by elevation of immunoglobulins IgA, IgM, IgE, and, particularly, IgG (hypergammaglobulinemia), with high levels of anti–HIV-1 antibody. This response may reflect both dysregulation of the T-cell suppression of B-cell antibody synthesis and active CD4 enhancement of the B-lymphocyte humoral response. As a result, the antibody response to routine childhood vaccinations may be abnormal. The B-cell dysregulation precedes the CD4 depletion in many children and may serve as a surrogate marker of HIV infection in symptomatic children in whom specific diagnostic tests (PCR, culture) are not available or are too expensive. Despite the increased levels of immunoglobulins, some children lack specific antibodies or protective antibodies. Hypogammaglobulinemia is very rare (<1%).

Central nervous system (CNS) involvement is more common in pediatric patients than in adults. Macrophages and microglia play an important role in HIV neuropathogenesis, and data suggest that astrocytes may also be involved. Although the specific mechanisms for encephalopathy in children are not yet clear, the developing brain in young infants is affected by at least two mechanisms. The virus itself may directly infect various brain cells or cause indirect damage to the nervous system by the release of cytokines (IL-1α, IL-1β, TNF-α, IL-2) or reactive oxygen damage from HIV-infected lymphocytes or macrophages.

Clinical Manifestations

The clinical manifestations of HIV infection vary widely among infants, children, and adolescents. In most infants, physical examination at birth is normal. Initial symptoms may be subtle, such as lymphadenopathy and hepatosplenomegaly, or nonspecific, such as failure to thrive, chronic or recurrent diarrhea, respiratory symptoms, or oral thrush and may be distinguishable only by their persistence. Whereas systemic and pulmonary findings are common in the United States and Europe, chronic diarrhea, pneumonia, wasting, and severe malnutrition predominate in Africa. Clinical manifestations found more commonly in children than adults with HIV infection include recurrent bacterial infections, chronic parotid swelling, lymphocytic interstitial pneumonitis (LIP), and early onset of progressive neurologic deterioration; note that chronic parotid swelling and LIP are associated with a slower progression of disease.

The CDC Surveillance Case Definition for HIV infection is based on the age-specific CD4 ⁺ T-lymphocyte count or the CD4 ⁺ T-lymphocyte percentage of total lymphocytes ( Table 302.1 ), except when a stage 3–defining opportunistic illness ( Table 302.2 ) supersedes the CD4 data. Age adjustment of the absolute CD4 count is necessary because counts that are relatively high in normal infants decline steadily until age 6 yr, when they reach adult norms. The CD4 count takes precedence over the CD4 T-lymphocyte percentage, and the percentage is considered only if the count is unavailable.