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1240 Part IX: Lymphocytes and Plasma Cells Chapter 81: Hematologic Manifestations of Acquired Immunodeficiency Syndrome 1241

needle sharing 0.63 percent, for needle stick 0.23 percent, for receptive systemic inflammatory state leads to tissue fibrosis over time 43,44 that
anal intercourse 1.38 percent, for insertive anal intercourse 0.11 percent, is partly responsible for immune failure and the increased frequency of
for receptive vaginal intercourse 0.08 percent, and for insertive vaginal nonimmune, nontraditional chronic diseases that now plague an aging
intercourse 0.04 percent. In 2012 there were an estimated 35.3 million HIV population. 45
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people living with HIV, including 2.3 million newly infected persons.
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Although the global incidence of HIV is thought to have peaked in 1997, CLINICAL FEATURES AND
the prevalence of HIV is increasing because of ongoing new infections
and the shrinking death rate of those already infected and on ART (2.3 DISEASE PROGRESSION
million deaths in 2005 versus 1.6 million deaths in 2012). The majority Primary HIV infection that comes to medical attention presents as a
of HIV-infected persons (approximately 23 million) now live in sub-Sa- febrile illness that may include headache, pharyngitis, lymphadenopathy,
haran Africa with 4 million in Asia and Southeast Asia and roughly 3 gastrointestinal symptoms, and rash and may be mistaken for mononu-
million in the Americas and Caribbean. cleosis or other nonspecific viral infections. Key to making the diagnosis
is taking a history for HIV risk factors and obtaining appropriate lab-
PATHOGENESIS oratory testing (combined HIV Ag/Ab assays and plasma HIV RNA
testing). However, in most cases, primary infection goes undiagnosed
Eighty percent of HIV infections occur via mucosal transmission dur- and patients are later identified in the chronic, asymptomatic phase of
ing sex when cell-free and cell-associated virions transverse the epi- infection by routine screening or later still, after the development of
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thelium to gain access to macrophages, Langerhans cells, dendritic cells, symptoms that are often caused by opportunistic infections. Typically,
and CD4-expressing T lymphocytes. To infect most cells HIV must the asymptomatic phase of chronic infection will last for 8 to 10 years,
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bind to CD4 and one of two major coreceptors (CCR5 or CXCR4); in although there is great interindividual variation dictated by the effective-
most cases, CCR5-utilizing viral strains are those that are transmitted ness of the immune response in controlling HIV replication (the viral
and predominate early in disease. Rare individuals who do not express “setpoint,” see above). Long-term nonprogressors (those who maintain
CCR5 (homozygote for a 32 bp deletion mutation in the CCR5 gene) CD4+ T-cell counts >500 for 5 years without therapy) and elite controllers
are highly resistant to HIV infection although they can be infected (those with low or nondetectable plasma HIV RNA without treatment)
with isolates utilizing CXCR4. After transmission, low-level replica- can live for decades with limited or no disease progression, while others
tion of HIV in tissue macrophages and dendritic cells can occur, but with high viral setpoints in the range of 100,000 to >1,000,000 copies/
the key role these cells play is in trapping and trafficking virions and mL can develop AIDS-defining illnesses quickly after primary infection.
presenting them to CD4+ T lymphocytes within regional lymphatics In untreated individuals CD4+ T-cell counts (typically at CD4 counts)
(e.g., gut-associated lymphoid tissue and lymph nodes where the infec- typically decline by 50 to 100 cells/μL per year, taking 8 to 10 years before
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tion is amplified). High-level viral replication proceeds within these counts are in the range where symptoms develop (typically at CD4 count
local tissues leading to profound CD4+ T-cell depletion, establish- <500 cells/μL) or AIDS-defining illnesses occur (typically at CD4 count
ment of a reservoir of latently infected memory T cells and eventually <200 cells/μL). Historically, opportunistic infections provided the first
to high plasma levels of virus that are the hallmark of acute infection. evidence for the existence of HIV and remain the most visible mani-
The immune response to HIV is brisk but ineffective and may, in fact, festation of infection in countries with limited access to ART and in
fuel the infection because the expression of inflammatory cytokines individuals who are diagnosed late in the course of their disease. The
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and migration of activated CD4+ T cells to the site of HIV-1 concentration development of opportunistic infections and AIDS-defining conditions
provides additional activated cells that the virus coopts for its own is dependent on the virulence properties of the organism and the degree
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replication. The initial antibody response to HIV does not contain of host immune suppression. Pathogens with high virulence potential
neutralizing antibodies; these develop only later, months after chronic (e.g., Mycobacterium tuberculosis, Salmonella sp., the bacterial agents of
infection is established. Furthermore, HIV escapes these antibodies by community-acquired pneumonia) cause disease in patients without HIV
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mutations within N-glycosylation sites that prevent antibody binding. and do so in HIV-infected persons regardless of CD4 count (although
The CD8+ cytotoxic T-lymphocyte (CTL) cell response to HIV controls more severe and prolonged illness occurs with more profound immu-
high-level viral replication during primary infection and establishes the nodeficiency). Agents with more limited pathogenic potential typically
viral “setpoint” or plasma level of HIV RNA in chronic infection. Evi- cause disease at lower CD4 counts, for example, P. jiroveci at CD4 counts
dence for the controlling anti-HIV effect of CD8+ T cells includes their below 200 cells/μL, while those that rarely cause disease in immunocom-
detection immediately prior to peak viremia, the development of viral petent persons, such as disseminated Mycobacterium avium complex,
escape mutations 28–30 and the requirement for CD8+ T cells to control Toxoplasma gondii encephalitis, and JC virus (the agent of progressive
SIV infection in Rhesus macaques. The rate of viral escape mutations multifocal leukoencephalopathy), typically occur only in those with
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slows during chronic infection 32,33 and is not associated with further very advanced HIV disease and CD4 counts less than 100 cells/μL or less
declines in viral load, reaching a stalemate where viral replication con- than 50 cells/μL , respectively (Table 81–1 lists HIV staging; Table 81–2
tinues under the pressure of a slowly evolving CTL response leading to
viral strains with reduced replication capacity. 34–36 As important as the TABLE 81–1. HIV Staging
direct cytolytic effect of HIV on CD4+ T cells, the virus induces a state
of chronic immune activation of both the adaptive and innate immune HIV Stage Description
systems that is central to disease pathogenesis. 37–41 Because the immune 0 Infection within the previous 6 months
response to HIV is defective and does not clear the virus, the immune 1 CD4 count ≥500 cells/μL (or ≥26%)
system remains continually activated with high rates of T-cell turnover
that eventually leads to T-cell exhaustion and depletion. This is particu- 2 CD4 count 200–499 cells/μL (or 14–25%)
larly evident in gut-associated lymphoid tissue where early T-cell losses 3 AIDS-defining condition or CD4 count
alter the integrity of the mucosal border leading to microbial translo- <200 cells/μL (or <14%)
cation and leakage of lipopolysaccharide (LPS) into the blood which, Unknown If none of the above apply
in turn, amplifies the state of immune activation. This persistent,
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