Central nervous system viral invasion and inflammation during acute HIV infection

Abstract

Background: Understanding the earliest central nervous system (CNS) events during human immunodeficiency virus (HIV) infection is crucial to knowledge of neuropathogenesis, but these have not previously been described in humans.

Methods: Twenty individuals who had acute HIV infection (Fiebig stages I-IV), with average 15 days after exposure, underwent clinical neurological, cerebrospinal fluid (CSF), magnetic resonance imaging, and magnetic resonance spectroscopy (MRS) characterization.

Results: HIV RNA was detected in the CSF from 15 of 18 subjects as early as 8 days after estimated HIV transmission. Undetectable CSF levels of HIV (in 3 of 18) was noted during Fiebig stages I, II, and III, with plasma HIV RNA levels of 285651, 2321, and 81978 copies/mL, respectively. On average, the CSF HIV RNA level was 2.42 log(10) copies/mL lower than that in plasma. There were no cases in which the CSF HIV RNA level exceeded that in plasma. Headache was common during the acute retroviral syndrome (in 11 of 20 subjects), but no other neurological signs or symptoms were seen. Intrathecal immune activation was identified in some subjects with elevated CSF neopterin, monocyte chemotactic protein/CCL2, and interferon γ-induced protein 10/CXCL-10 levels. Brain inflammation was suggested by MRS.

Conclusions: CSF HIV RNA was detectable in humans as early as 8 days after exposure. CNS inflammation was apparent by CSF analysis and MRS in some individuals during acute HIV infection.

Figure 1.

Plasma (squares) and cerebrospinal fluid (CSF; circles) human immunodeficiency virus (HIV) RNA levels, by infection duration. Cases with plasma HIV RNA level measured on the same day as lumbar puncture are represented by open squares, and cases with plasma HIV RNA measured at enrollment are represented by solid squares (median of 2 days before lumbar puncture).

Figure 2.

Cerebrospinal fluid (CSF) protein levels (open circles) and white blood cell (WBC) counts (solid triangles) in individuals with acute human immunodeficiency virus infection, by infection duration.

Figure 3.

Cerebrospinal fluid (CSF) inflammatory markers during acute human immunodeficiency virus (HIV) infection. CSF neopterin (A), monocyte chemotactic protein (MCP-1/CCL2; B), and interferon γ–induced protein 10 (IP-10/CXCL-10; C) levels, demonstrating cases with elevated levels, compared with published normative data among US, HIV-negative controls <45 years old. Long dashes indicate the mean value for HIV-negative controls, with shorter dashes denoting 1 and 2 SDs above the mean value. Fiebig stages are indicated by solid squares (for stage I), open circles (for stage II), solid triangles (for stage III, and open diamonds (for stage IV).

Figure 4.

Magnetic resonance spectroscopy for choline/creatine in basal ganglia (A) and occipital grey matter (B) in individuals with acute human immunodeficiency virus (HIV) infection, compared with individuals with chronic HIV infection and HIV-negative Thai controls.