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Acute HIV Infection Overview
      10/13/04 10:36 PM

1. Acute HIV-1 Infection
Marcus Altfeld and Bruce D. Walker


Introduction

Acute HIV-1 infection presents in 40 - 90 % of cases as a transient symptomatic illness, associated with high levels of HIV-1 replication and an expansive virus-specific immune response. With 14,000 new cases per day worldwide, it is an important differential diagnosis in cases of fever of unknown origin, maculopapular rash and lymphadenopathy.

The diagnosis of acute infection is missed in the majority of cases, as other viral illnesses ("flu") are often assumed to be the cause of the symptoms, and there are no HIV-1-specific antibodies detectable at this early stage of infection. The diagnosis therefore requires a high degree of clinical suspicion, based on clinical symptoms and history of exposure, in addition to specific laboratory tests (detection of HIV-1 RNA or p24 antigen and negative HIV-1 antibodies) confirming the diagnosis.

An accurate early diagnosis of acute HIV-1 infection is important, as patients may benefit from therapy at this early stage of infection (see below), and infection of sexual partners can be prevented.



Immunological and virologic events during acute HIV-1 infection


During acute HIV-1 infection, the virus is replicating extensively in the absence of any detectable adaptive immune response, reaching levels of up to 100 million copies HIV-1 RNA/ml. It is during this initial cycle of viral replication that important pathogenic processes are thought to occur. These include the seeding of virus to a range of tissue reservoirs and the destruction of HIV-1-specific CD4+ T lymphocytes. The very high levels of HIV-1 viremia are normally short-lived, indicating that the host is able to generate an immune response that controls viral replication. Over the following weeks, viremia declines by several orders of magnitude before reaching a viral setpoint. This set-point following resolution of the acute infection is a strong predictor of long term disease progression rates [1].

Several factors can influence viral replication during acute infection and the establishment of a viral setpoint. These include the fitness of the infecting virus, host genetic factors and host immune responses. While antibodies against HIV-1 with neutralizing capacities are rarely detectable during primary HIV-1 infection, a number of studies have demonstrated a crucial role of HIV-1-specific cellular immune responses for the initial control of viral replication during this stage of infection. A massive, oligoclonal expansion of CD8+ T cell responses has been described during acute HIV-1 infection [2], and the appearance of HIV-1-specific CD8+ T cells has been temporally associated with the initial decline of viremia [3, 4]. These CD8+ T cells have the ability to eliminate HIV-1-infected cells directly by MHC class I-restricted cytolysis or indirectly by producing cytokines, chemokines or other soluble factors, thus curtailing the generation of new viral progeny [5]. The biological relevance of HIV-1-specific cytotoxic T cells (CTL) in acute HIV-1 infection was highlighted in recent in-vivo studies demonstrating a dramatic rise of SIV viremia and an accelerated clinical disease progress in macaques after the artificial depletion of CD8+ T cells [6, 7]. Additional evidence for the antiviral pressure of HIV-1-specific CTLs during primary HIV-1 infection has been provided by the rapid selection of viral species with CTL epitope mutations that were detected within a few weeks after HIV-1 and SIV infection in humans and rhesus macaques, respectively [8, 9, 10].


During acute HIV-1 infection, the number of CD4+ T cells decline, occasionally to levels that allow the development of opportunistic infections at that time [11, 12]. Even though the CD4+ T cell count rebounds with the resolution of primary infection, it rarely returns to baseline levels in the absence of antiretroviral therapy. In addition to the decline in CD4+ T cell counts, qualitative impairments of CD4+ T cell function are perhaps the most characteristic abnormalities detected in HIV-1 infection. The impairment of HIV-1-specific CD4+ T cell function occurs very early in acute infection [13, 14], potentially due to the preferential infection of virus-specific CD4+ T cells by the virus [15]. This is followed by a functional impairment of CD4+ T cell responses to other recall antigens, as well as a reduced responsiveness to novel antigens [16].


In addition to host immune responses, host genetic factors play an important role in both susceptibility and resistance to HIV-1 infection and speed of disease progression following infection. The most important of these is a deletion in the major co-receptor for entry of HIV-1 into CD4+ T cells, a chemokine receptor called CCR5 [17]. Homozygotes for this 32 base pair deletion (CCR5delt32) do not express the receptor at the cell-surface and can only be infected with HIV strains that are able to use other co-receptors, such as CXCR4. Thus, although CCR5delta32 homozygotic individuals show a significant degree of resistance to HIV-1 infection [17], a number of cases of infection with CXCR4-using HIV-1 strains have been described [18, 19]. Heterozygotes for the deletion exhibit significant lower viral setpoints and slower progression to AIDS. In addition to mutations in the chemokine receptor genes, a number of HLA class I alleles have been described to be associated with both, lower viral setpoints and slower disease progression, including HLA-B27 and -B57 [20, 21]. Recent studies demonstrated that individuals expressing HLA-B57 presented significantly less frequently with symptomatic acute HIV-1 infection and exhibited a better control of viral replication following acute infection (Altfeld et al, AIDS 2003, in press). These data demonstrate that host genetic factors can influence the clinical manifestations of acute HIV-1 infection and have an important impact on subsequent viral setpoints and the speed of disease progression.



Signs and symptoms

After an incubation period of a few days to a few weeks after exposure to HIV, most infected individuals present with an acute flu-like illness. Acute HIV-1 infection is a very heterogeneous syndrome and individuals presenting with more severe symptoms during acute infection and a longer duration of the acute infection syndrome tend to progress more rapid to AIDS [22, 23, 24, 25, 26, 27]. The clinical symptoms of acute HIV-1 infection were first described in 1985 as an illness resembling infectious mononucleosis [28]. The most common symptoms (see Table 1) are fever, maculopapular rash, oral ulcers, lymphadenopathy, arthralgia, pharyngitis, malaise, weight loss, aseptic meningitis and myalgia [29]. In a recently published study by Hecht et al. [30], fever (80 %) and malaise (68 %) had the highest sensitivity for clinical diagnosis of acute HIV-1 infection, whereas loss of weight (86 %) and oral ulcers (85 %) had the highest specificity. In this study, the symptoms of fever and rash (especially in combination), followed by oral ulcers and pharyngitis had the highest positive predictive value for diagnosis of acute HIV-1 infection. In another study by Daar et al. [31], fever, rash, myalgia, arthralgia and night sweats were the best predictors for acute HIV-1 infection.


Table 1: Main symptoms of acute HIV-1 infection

Symptom
Frequency
Odds ratio (95% CI)

Fever
80%
5.2 (2.3-11.7)

Rash
51%
4.8 (2.4-9.8)

Oral ulcers
37%
3.1 (1.5-6.6)

Arthralgia
54%
2.6 (1.3-5.1)

Pharyngitis
44%
2.6 (1.3-5.1)

Loss of appetite
54%
2.5 (1.2-4.8)

Weight loss > 2.5 kg
32%
2.8 (1.3-6.0)

Malaise
68%
2.2 (1.1-4.5)

Myalgia
49%
2.1 (1.1-4.2)

Fever and rash
46%
8.3 (3.6-19.3)

From: Hecht FM et al. Use of laboratory tests and clinical symptoms for identification of primary HIV infection. AIDS 2002, 16: 1119-1129



The symptomatic phase of acute HIV-1 infection lasts between 7 - 10 days, and rarely longer than 14 days. The nonspecific nature of the symptoms poses a great challenge to the clinician and underlines the importance of a detailed history of exposure.

Diagnosis

The diagnosis of acute HIV-1 infection is based on the detection of HIV-1 replication in the absence of HIV-1 antibodies, as these are not yet present at this early stage of infection. Different tests are available for diagnosis of acute HIV-1 infection. The most sensitive tests are based on detection of plasma HIV-1 RNA.

In a recently published study [30], all assays for HIV-1 RNA that were tested (branched chain DNA, PCR and GenProbe) had a sensitivity of 100 %, but occasionally (in 2 - 5 % of cases) led to false positive results. False positive results from these tests are usually below 2,000 copies HIV-1 RNA per ml plasma, and therefore far below the high titers of viral load normally seen during acute HIV-1 infection (in our own studies on average 13 x 106 copies HIV-1 RNA/ml with a range of 0.25 - 95.5 x 106 copies HIV-1 RNA/ml). Repetition of the assay for HIV-1 RNA from the same sample with the same test led to a negative result in all false positive cases. Measurement of HIV-1 RNA from duplicate samples therefore results in a sensitivity of 100 % with 100 % specificity. In contrast, detection of p24 antigen has a sensitivity of only 79 % with a specificity of 99.5 - 99.96 %. The diagnosis of acute HVI-1 infection must be subsequently confirmed with a positive HIV-1 antibody test (seroconversion) within the following weeks.

During acute HIV-1 infection, there is frequently a marked decrease of CD4+ cell count, which later increases again, but usually does not normalize to the initial levels. In contrast, the CD8+ cell count rises initially, which may result in a CD4+/CD8+ ratio of < 1. Infectious mononucleosis is the most important differential diagnosis. Hepatitis, influenza, toxoplasmosis, syphilis and side effects of medications may also be considered.


In summary, the most important step in the diagnosis of acute HIV-1 infection is to include it in the differential diagnosis. The clinical suspicion of an acute HIV-1 infection then merely requires performance of an HIV-1 antibody test and possibly repeated testing of HIV-1 viral load, as shown in the algorithm in Figure 1 (adapted from [30]).


Figure 1: Algorithm for the diagnosis of acute HIV-1 infection




Treatment

The goal of antiretroviral therapy during acute HIV-1 infection is to reduce the number of infected cells, preserve HIV-1-specific immune responses and possibly lower the viral set point in the long term. Several studies in recent years have shown that treatment of acute HIV-1 infection allows long-term viral suppression, leads to preservation and even increase of HIV-1-specific T helper cell responses and allows for the conservation of a very homogeneous virus population.

First pilot studies in patients who were treated during acute HIV-1 infection and subsequently went through structured treatment interruptions show that the HIV-1-specific immune response could be boosted in these patients [32]. Most patients were subsequently able to discontinue therapy and experienced at least temporal control of viral replication, with viral set points remaining below 5,000 copies/ml for more than 3 years in some patients. However, in a large number of individuals (>50%) in this study, as well as in other studies assessing viral control following treated primary infection [33], viral load rebounded during longer follow-up, requiring the initiation of therapy.

The long-term clinical benefit of early initiation of therapy has not been demonstrated yet. It is also not known how long the period between acute infection and initiation of therapy can be without losing immunological, virological and clinical benefit. In view of all these unanswered questions, patients with acute HIV-1 infection should be treated in controlled clinical trials [34]. If this is not possible, the option of standard first-line treatment should be offered and discussed. Usually, treatment continues for at least a year, followed by structured treatment interruptions within the framework of controlled studies or other immunotherapeutic intervention. It is important during counseling to clearly indicate the lack of definitive data on clinical benefit and to address the risks of antiretroviral therapy and treatment interruptions, including drug toxicity, development of resistance, acute retroviral syndrome during viral rebound and HIV-1 transmission and superinfection during treatment interruptions.


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