The neuropathogenesis of HIV‐1 infection

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Significant neurological complications associated with HIV-1 infection occur years after an acute viral seroconversion reaction and are commonly coincident with progressive immunosuppression and high viral loads. Disease processes start soon after initial viral infection, initiated through the exchange of infected body fluids by blood transfusion, accidental needle sticks, sexual intercourse, and maternal–fetal transmission. Infection is highly restricted for varying time periods, but is usually measured in years. The evasion of the innate and acquired immune surveillance mechanisms leads to dissemination and high-level replication to regional lymphatics and HIV-1 target tissues, including the bone marrow, lung, and brain. Importantly, HIV-1 enters the central nervous system (CNS) early in the course of disease. The virus is carried into the brain principally through CD4 T lymphocytes and mononuclear phagocytes (MPs), dendritic cells, monocytes, and macrophages. Following acute infection the host engages the virus in a commensal relationship. This allows a subclinical stage in which HIV-1 persists in the infected human host but at low levels. The most severe form of HIV-1-associated tissue damage occurs in the CNS. The lack of adequate innate viral control mechanisms and adaptive immunity allows active viral replication to occur in the brain.

Introduction

Significant neurological complications associated with HIV‐1 infection occur years after the acute viral seroconversion reaction and is commonly coincident with progressive immunosuppression and high viral loads. Disease processes start soon after initial viral infection, initiated through exchange of infected body fluids by blood transfusion, accidental needle sticks, sexual intercourse and maternal–fetal transmission (Royce 1997, Lackritz 1998, Newell 1998, Beltrami 2000). Infection is “highly” restricted for varying time periods but usually measured in years (Krishnakumar et al., 2005). Evasion of the innate and acquired immune surveillance mechanisms leads to dissemination and high‐level replication to regional lymphatics and HIV‐1 target tissues, including the bone marrow, lung and brain. Importantly, HIV‐1 enters the central nervous system (CNS) early in the course of disease (Davis 1992, An 1999). Virus is carried into the brain principally through CD4 T lymphocytes (Haase, 1999) and mononuclear phagocytes (MPs), dendritic cells, monocytes and macrophages (Tardieu and Boutet, 2002).

Following acute infection the host engages the virus in a commensal relationship. This allows a subclinical stage in which HIV‐1 persists in the infected human host but at low levels. Virus persists in CD4 T lymphocytes and cell death occurs as a result of active replication. The destroyed CD4 T lymphocytes are replaced by new bone marrow‐derived cells. Inevitably, as disease progresses, the birth of new cells cannot replace those destroyed by virus and immune suppression ensues with uncontrolled viral growth and the breakdown of adaptive antiretroviral immune surveillance mechanisms (Ho 1995, Krishnakumar 2005). CD4 T lymphocyte depletion may also occur as a consequence of HIV‐1‐induced deficits in hematopoiesis by preventing production of new lymphocytes. Here, viral glycoproteins and inflammatory cytokines can impair bone marrow cell repopulation functions (Geissler 1991, Maciejewski 1994, Douek 1998). The lymphopenia that occurs affects the host's ability to combat a broad spectrum of opportunistic infections and neoplasms and HIV‐1‐associated tissue damage ensues.

The most severe form of HIV‐1‐associated tissue damage occurs in the CNS. The lack of adequate innate viral control mechanisms and adaptive immunity allows active viral replication to occur in brain. Here, a metabolic encephalopathy results as a consequence of continued and uncontrolled brain MP (perivascular macrophage and microglia) infection and immune activation (Anderson et al., 2002). The length of time prior to the development of CNS disease and its associated profound immune suppression has increased following the institution of highly active antiretroviral therapy (HAART) (d'Arminio Monforte 2000, Yang 2004). However, in patients without therapy or those that respond poorly to it, the immune system is damaged and disease occurs (Ho 1995, Wei 1995, Krishnakumar 2005). When the numbers of CD4 T lymphocytes drop below 200/μl patients not only become susceptible to opportunistic infections but also to virus induced tissue injury including, most notably, HIV‐associated dementia (HAD).

Section snippets

Epidemiology of HAD in the era of HAART

Incidence, prevalence and severity of HIV‐1‐associated neurocognitive disorders have changed remarkably in the past decade following the advent of HAART. In the early 1990s the prevalence of HAD was between 20 and 30% of individuals with advanced disease with CD4 T lymphocyte counts of less than 200/μl (Navia 1986, McArthur 2003). The introduction of HAART increased life expectancy and decreased severity and incidence of HAD to ≤10% in HIV‐infected people (Dore 1997, Ferrando 1998, Sacktor 2001

Viral receptors and infection

Cellular susceptibility to HIV‐1 infection is regulated by CD4, CXCR4 and CCR5 receptor expression on virus target cells. HIV‐1 enters CD4 T lymphocytes by fusion at the plasma membrane after interactions with CD4 and a co‐receptor. The identity of the co‐receptor determines HIV‐1 macrophage or T cell tropism (M‐ or T‐tropic). The genetic polymorphism in the HIV‐1 envelope glycoprotein gp120 underlies co‐receptor usage and the host cell type infected. The hypervariable region at V3 loop of

Viral load in the brain: disease progression and immune suppression

HIV‐1 infection induces effective cell‐mediated and humoral immune responses, which, in the earliest stages of disease, curbs HIV‐1 infection (Krishnakumar et al., 2005). Indeed, HIV‐1 antibodies and the virus itself can be detected in the CSF during primary HIV‐1 infection (Ho 1985, Goudsmit 1986). The initial protective response to HIV‐1 infection comes from CD8 cytotoxic T cells. CD4 T helper cells affect B cell activation/differentiation and the production of antibodies as well as a variety

Neurotoxic output of brain MP

MPs are a significant source of neurotoxins during disease (Gabuzda 1986, Koenig 1986, Genis 1992). Microglia represent up to 10% of the parenchymal brain cell population in some regions. Neighboring elliptical microglia contact each other in series and in parallel, forming a network. Recent studies, by several groups, support the idea that perivascular macrophages are preferentially infected and pose the greatest threat as sources of neurotoxic activities (Pulliam 1997, Rappaport 2001,

Bioimaging for monitoring inflammation and neurodegeneration

The HIV‐1‐associated brain inflammation can be visualized through the use of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) (Boska et al., 2004), two very promising techniques for examining the effect of HAD on brain metabolites and functioning. MRS can detect and measure multiple metabolites in the brain, including: N‐acetyl (NA)‐containing compounds (predominantly N‐acetyl aspartate), choline‐containing compounds, glutamate and glutamine, and myoinositol (MI). The

Adjunctive therapies

The goal of adjunctive therapies is the treatment and prevention of HAD and MCMD (Dou et al., 2004) through minimizing the cell damage that occurs with HIV‐1 infection of the brain, such as lithum chloride and valproic acid (Dou 2003, Dou 2004). An understanding of how cells of the CNS are damaged and how such damage can lead to CNS dysfunction upon HIV‐1 infection has identified new therapeutic targets for adjunctive therapies. Enhancing the protective action of neurotrophins (Bachis et al.,

Potential biomarkers in CSF and plasma for HAD

As previously stated, HIV‐1 replication is tightly controlled in the brain for years following initial infection (Navia et al., 1986). The underlying molecular mechanisms of innate CNS immune responses regulating viral replication and influencing MP neurotoxic reactions are not completely understood. A critical question in the pathogenesis of HAD is what instigates high levels of viral replication late in the course of disease. Productive viral infection of brain MP is necessary but not

Future prospects for the neuropathogenesis of HIV‐1 infection

The neuropathogenesis of HIV‐1 infection revolves around inflammatory factors secreted from virus‐infected and immune‐competent brain MPs. This classic view of HAD has undergone some re‐evaluation in the post‐HAART era. Diagnostic tools for neurocognitive disorders will likely be improved through the use of advanced brain imaging techniques. In particular, understanding the molecular mechanism of MP activation by characterizing cell‐specific molecules will aid in biomarker discoveries.

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