Different HIV treatment drugs stop the virus fusing, stop it integrating its genetic code, and stop it releasing new copies of itself into the bloodstream. Would you like to comment on this page? Although the long-term persistent replication of virus leads to immunodeficiency, the damage to the host that leads to this state must be multifactorial.
Loss of the capacity to make T cells and loss of the support structure to mature and regulate T cells may also contribute to the loss of immunologic capacity. The onset of immunodeficiency sets the stage for opportunistic infections by common microbes that are otherwise controlled by the healthy host.
The virus contributes to this phenomenon as shown by the appearance of variants that allow the virus to replicate in new cell types. At any one time, the virus is limited to cell types in which it can maintain a steady-state infection that is not cleared by the immune system. Growth in alternative cells likely is a challenge for the virus because replication in suboptimal cell targets would likely result in slow replication and easier containment by the immune system. With immunodeficiency the host response to replication in alternative cell types would be slower, giving the virus a chance to adapt to the new environment.
However, in the clearest cases the virus stays close to home in that it always requires CD4, but can adapt to use lower levels, and it at most swaps one chemokine coreceptor for another, CXCR4 for CCR5. Whether the virus can evolve beyond these limits in an infected host is unknown but the tools for finding such viruses are in place. In this article we follow the virus from transmission through dissemination and the adaptation to new target cells late in infection.
Some of the ideas overlap other articles, which we have cited and which can be consulted for more detail. Still, the potential for the virus to participate in pathogenic processes beyond immunodeficiency make such questions relevant. Transmission is covered at length by Shaw and Hunter There are several aspects of transmission that influence viral pathogenesis. Under these circumstances, it is understandable that the infecting dose is a single virus particle; that is, limiting rates of infection result in infection with the minimal infectious dose.
This inference has largely been confirmed with the molecular analysis of HIV-1 present after acute infection.
In most cases, systemic infection is established by a single genetic variant in sexual transmission, transmission by intravenous drug use, or vertical transmission, although the frequencies of single variant versus multiple variant infections may vary by route see Shaw and Hunter There is ongoing discussion about where the genetic bottleneck associated with transmission occurs. There may be compartmentalization and restriction of the population in the donor at the site that produces the transmitted virus, although there is little evidence in support of this see below.
Alternatively, there may be physical barriers that limit the exposure in the recipient to very small amounts of virus; such barriers might include mucus and epithelium in the genital tract, which would limit access of virus to susceptible cells. Finally, multiple cells could become infected at the site of transmission, but only one variant succeed in establishing a systemic infection. There are rare examples in which the initially observed virus is not the same as the transmitted virus Kim et al.
There are several steps in the life cycle of HIV that can happen over many years. HPTN clinical trial Non-macrophage-tropic human immunodeficiency virus type 1 R5 envelopes predominate in blood, lymph nodes, and semen: Natural killer cell infection and inactivation in vitro by the human immunodeficiency virus. Annual Review of Medicine. The viral Nef protein has been implicated in dysregulation of cell function through interaction with cellular signaling cascades Husain et al. A combination of at least three ART drugs is needed to suppress the virus from replicating and boost the immune system.
However, in the setting of low frequency infection in humans, transmission of a single variant appears to be the norm Shaw and Hunter An early observation important for understanding viral pathogenesis was that some viruses isolated from people late in infection were able to grow and cause syncytia in transformed T-cell lines Asjo et al. The remaining viruses were dubbed nonsyncytium-inducing NSI. These NSI viruses were found early in infection and had some capacity to infect macrophages. More recently, it was discovered that only a fraction of viruses that use CCR5 can infect macrophages because of the low levels of surface CD4 see below and these are not the transmitted viruses.
Indeed, viruses with macrophage-tropic Env proteins appear only late in infection, calling into question the role of macrophage infection in systemic infection. Thus the transmitted virus typically uses CCR5 and replicates in activated T cells as evidenced by its need for high levels of surface CD4 Isaacman-Beck et al.
In any case, there is little evidence to suggest that viral replication in DCs is an important part of the mechanism of transmission. There are several potential mechanisms for the virus to move from a localized infection to a systemic infection. The simplest model is that the concentration of virus is sufficiently high in the extracellular space to diffuse to adjacent target cells and tissues.
Alternatively, virus could be transported by dendritic cells to proximal lymphoid tissue. Similarly, infected T cells could migrate to different body compartments to deliver virus. It will be important to place this binding property of Env in the context of a large sampling of transmitted viruses to determine the frequency of this property. CD4 is required for natural isolates of HIV-1 to infect cells. Thus, robust infection of cells is limited to those expressing CD4. Other cell types can express lower levels of CD4, for example monocytes and macrophages, and it has been reported that CD4 plays an alternative role as the receptor for IL Liu et al.
However, these studies have relied on linking the presence of viral DNA to cell surface markers, as opposed to using a marker of active viral replication. In cell culture HIV-1 infects activated cells with much greater efficiency than quiescent cells Korin and Zack , with central and effector memory cells as the primary targets Pfaff et al. The appearance of CXCR4-using viruses X4 viruses is correlated with more rapid progression of disease, but it is still unclear if the evolution of these variants is the cause or a marker of rapid disease progression Schuitemaker et al.
Both may be true. Although R5-to-X4 evolution is common, it is not essential for progression to disease.
An accumulation of basic amino acid substitutions at specific positions in the V3 loop of SU is associated with the coreceptor switch, which is presumed to increase specificity or affinity for CXCR4 Wilen et al. There are other positions in Env but outside of V3 that also contribute to the X4 phenotype, but the specific contribution of these other sites is not clear Hoffman et al. There also seem to be differences among the subtypes for their propensity to evolve X4 variants, with X4 variants being more common in subtype D isolates Tscherning et al.
The reason for this difference is unclear, although the evolutionary distance between R5 and X4 variants of each subtype might be different. Conversely, X4 variants of subtype C appear to evolve less frequently and often include more dramatic sequence changes in V3, including deletions, compared to the sequence changes seen in subtype B Coetzer et al. Monocytes are found in the blood and migrate to tissue where they differentiate into macrophages. This can be mimicked in cell culture by differentiating isolated blood monocytes into macrophages monocyte-derived macrophages MDM by exposure to cytokines.
Monocytes and dendritic cells isolated from blood express very low levels of CD4 Lee et al. Peripheral monocytes have been reported to be infected in vivo Zhu et al. However, a recent analysis of viral DNA in blood cell subsets failed to detect a significant amount of viral DNA in the monocyte pool Joseffson et al. Infection of monocytes in vitro is limited by the low levels of surface CD4 and blocks to entry Arfi et al. Macrophage-tropic viruses infect cells with low levels of surface CD4 Gorry et al.
The only place where there is clear evidence for the evolution of these viruses is in the brain, where at least a fraction of the cases of HIV-associated dementia involve the presence of macrophage-tropic virus see Spudich and Gonzalez-Scarano There are two potential cell targets in the brain, microglia cells macrophage-like cells in the parenchyma , and perivascular macrophages that migrate into the brain as part of an inflammatory response.
It is not known which cell type supports the evolution and replication of macrophage-tropic viruses in the central nervous system CNS. In addition to detecting these viruses in brain tissue at autopsy, it has now been possible to link the slow decay of virus in the CSF during therapy Ellis et al. It has been possible to isolate viruses from blood that can enter macrophages Li et al. However, these are not the viruses that evolve in the CNS, which are absent from the blood Schnell et al.
Understanding the range of infection in the body by macrophage-tropic viruses will require sampling different tissues but under conditions of more extensive disease progression to look for these late-evolving variants. Both X4 viruses and macrophage-tropic viruses evolve from R5 progenitors, which require high levels of CD4, as found on activated T cells.
Both of these variants appear late in the disease course and are therefore linked to increasing immunodeficiency of the host. Neither is efficiently transmitted. Thus, they both appear to be evolutionary dead-ends that evolve anew in each host, representing the extension of infection into new cell types Fig. One evolutionary model is based on adaptation of the Env protein structure in response to a changing host environment Cheng-Mayer et al. This model suggests that in the presence of a weakened antibody response, the Env protein can evolve to be in a more open conformation rather than the closed, neutralization-resistant conformation that avoids sensitivity to antibodies targeting the coreceptor binding face.
This concept is shown in Figure 2 , in which the evolution of the open conformation may allow faster entry into T cells but also potentiate interaction with CXCR4 and the ability to enter cells with lower levels of CD4, setting the stage for further evolution. Time course of a typical HIV-1 infection with the appearance of host range variants late. The time course for different components of the infection are shown. There is an initial viremia of the transmitted virus that uses CCR5 R5 and requires high levels of CD4 to enter cells, and this virus establishes a set point during the period of clinical latency CD4 Hi R5 T-cell-tropic, green line.
Evolution of host range variants.
In this model the variant of HIV-1 that is replicating in memory T cells requiring high levels of CD4 on the surface of the cell and using CCR5 as the coreceptor, shown in green is exposed to reduced host surveillance in the form of reduced selective pressure from antibodies. This allows the virus to evolve such that the Env protein assumes a more open conformation that allows increased binding to CD4. The open conformation may also expose a latent low level tropism for CXCR4.
These changes potentiate the subsequent evolution to use CXCR4 efficiently X4 virus—red or to use CD4 more efficiently macrophage tropism—blue. NK cells can also be infected in vitro, although with a limited range of viruses Robinson et al. Viral DNA can also be found in this cell lineage in vivo Valentin et al. Thus, the virus is broadly disseminated in the body. Given this wide distribution, it is not clear what the source of virus is in the blood, from which viral samples have been most extensively studied. It is not clear whether the virus in the blood is produced by infected cells in tissue or in blood, or if all virus-producing tissues shunt virus into the blood with equal efficiency.
Studies of tissues require biopsy or analysis of autopsy material, preventing careful time course studies, and the analysis of viral sequences is usually of DNA, which can include archival and defective viral DNA that may not represent the currently replicating virus. Also, free virus, the most sensitive and reliable instantaneous indicator of the state of infection, is not accessible from solid tissue samples. For this reason, more accessible fluids such as semen, cervico-vaginal mucus, and cerebral spinal fluid are often used as surrogates for the corresponding tissue.
Genetic analysis of virus from tissues or their liquid surrogates has generated several unifying observations. In many cases the genetic diversity of the viral population in the blood overlaps the population in the tissue, suggesting a well-mixed relationship in which the virus in the blood is derived from that tissue or imported into the tissue, and if imported into the tissue the virus must undergo little replication given its similarity to the virus in the blood. A variation on the mixing includes a specific lineage of the virus in the compartment disproportionately and transiently expanding, resulting in clonal expansion or amplification of a subset of viral sequences.
In a third scenario, the viral population in a tissue can be distinct from the virus in the blood, indicating an independently replicating population that is not exchanging between the compartments. Examples of these types of genetic relationships are shown in Figure 3 comparing blood and semen, taken from Anderson et al. One unifying model is that for many tissues virus is imported by some mechanism from the blood compartment at a low level, giving the appearance of equilibrated populations.
Only when local viral replication reaches a level in which it significantly increases the local viral RNA load does it become apparent that there is an independently replicating population that can be recognized as genetically distinct. Phylogenetic trees demonstrating different relationships between viral populations.
In these trees are examples of viral populations in blood red and semen blue. On the left is an example of well-mixed populations with the sequences derived from blood and semen intermingled. In the middle is an example of clonal amplification blue bars in which a nearly homogeneous set of sequences appears only in the semen creating a population that is distinct from the blood. On the right is an example of compartmentalization in which the sequences in the semen are distinct from the bulk of the sequences in the blood.
These two lineages are indicated by the circles. In addition, sequences present in the seminal tract appear to have migrated back into the blood compartment. These trees were originally published in Anderson et al.
The use of cDNA end point dilution followed by multiple PCR amplifications also called single genome sequencing or single genome amplification avoids both PCR resampling which results in artifactual population homogeneity and PCR-mediated recombination which confounds the genetic structure of the population and therefore provides the most reliable source of sequences for the analysis of issues dealing with viral population structure. Viral populations in the blood tend to be complex genetically, consistent with a large and diverse population.
Genetic variants within this population decay at similar rates, including both X4 and R5 variants, indicating that the virus-producing cells have mostly similar half-lives Ince et al. One exception is a small percentage of infected cells that appear to be slow to integrate viral DNA, so that when an integrase inhibitor is used an even larger fraction of the viral load is accounted for in cells with a short half-life Murray et al. A small fraction of the virus in the blood decays with much slower kinetics.
The significance of these populations is discussed by Coffin and Swanstrom and Siliciano and Greene In addition, there is a diffuse distribution of virus trapped on follicular dendritic cells throughout the lymph node Lackner et al. The high efficiency of virus spread between cells has the potential to generate overlapping foci of clonal infection, resulting in local spread of a genetically homogeneous population Gratton et al.
In this view the virus creates many independent sites of replication in lymphoid tissue driven by high local concentrations of virus, with the complex population seen in the blood the sum of production from all of these independent foci. This effect could limit the chance for recombination to sites of overlapping foci, or require virus produced at distal sites to colonize new tissues to allow encounter of new recombination partners. The current government procurement procedures are tedious and slow, which causes further delay in research. What are your thoughts on the move to amend the existing HIV law and lower the age of HIV testing without parental consent to 15?
This is long overdue.
This approach is meant to help identify persons living with HIV who may otherwise not volunteer or subject themselves to testing because they do not think that they are at risk of HIV infection. Condoms have always been a hard sell in conservative, Catholic Philippines. What are your thoughts on how to aggressively promote condoms in HIV prevention?
Condoms are collateral damage resulting from the Catholic Church's stand on contraception and if we can get away from that label and present it as a health promotion and prevention tool — which it is anyway — it might be more acceptable. Philippine workers infected by HIV suffer workplace discrimination on account of their health status and usually do not seek redress, revealed a new report released by Human Rights Watch today.
At its current rate, the total number of HIV infections could reach , by Santos reports from Manila. Santos reports on an epidemic partly driven by shame. Nations around the world have said they're ready to commit billions to eradicate tuberculosis. But the deal only came about after countries denied US-proposed changes to protect pharmaceutical companies. Gone are the days when gonorrhea was associated with dark alleyways and backstreet brothels. Today, it's clear that anyone can become infected — and fast.